Histology

Liver

The liver is an accessory digestive gland. It develops as an outgrowth of the entodermal epithelium of the duodenum. The connection between the duodenum and liver develops as a bile duct. The liver is the largest gland in the body weighing about 1500 g.

It has a double blood supply, i.e., the arterial blood from hepatic arteries and venous blood from the veins of digestive tubes and spleen through portal vein.

Blood from both the sources (arterial and venous) passes through liver sinusoids and ultimately drains into hepatic veins that join the inferior vena cava. Thus, the substances absorbed from the intestines first come in contact with the liver cells.

Gross Histological Organization of Liver

The liver is surrounded by a thin connective tissue capsule and is divided into many lobes, i.e., left, right, caudate and quadrate lobes.

• The hepatic artery, bile duct and portal vein enter the liver at the porta (hilus-a short transverse fissure on the inferior surface of the liver). Artery and veins repeatedly branch to supply hepatic lobules.
• Although the bile duct also follows the same course, it carries bile in the opposite direction, i.e., away from liver lobules.
• The connective tissue entering the liver at the porta, along with other structures, branches within the liver to form the partial boundary of liver lobules and to support the branching vessels and ducts.
• In humans, the lobules of the liver are not well defined because their interlobular connective tissue is poorly developed. The interlobular connective tissue is also called interlobular septa.
• The branches of the portal vein, hepatic artery and bile duet course together in the connective tissue interlobular septa as a triad, called as a portal triad.

Microscopic Organization of Liver

1. Liver Lobule

The substance of the liver is made up of liver lobules that form the structural and functional unit of the organ. In cross¬section, the shape of a liver lobule is somewhat similar to a hexagon.

In the human liver, the connective tissue between adjacent lobules is scanty. Hence, no well-defined separation between adjacent lobules is seen. Therefore, the liver tissue of one lobule merges with that of adjacent lobules

At the corners (angles) of the hexagon (lobule) there are small triangular areas of the connective tissue that contain portal triads (branches of the portal vein, hepatic artery and an interlobular bile duct. Thus around the periphery of each lobule, there are several portal triads.

As the boundaries of hexagonal lobules are touching each other, every portal triad forms a partial boundary for more than one lobule. In the centre of each hepatic lobule is a central vein  The central vein drains blood from lobules into hepatic veins. Radiating from the central vein are hepatic cells (hepatocytes), which are arranged in plates (laminae) that are usually one cell thick. These plates anastomose to form a three-dimensional network.

Between the plates (laminae) are blood passageways called sinusoids. The lateral branches of the small hepatic artery and portal venules, which arise from the portal triads, join to form the hepatic sinusoids. The flow of blood in sinusoids is from the periphery of the lobule to toward the central vein.

The bile canaliculus is a small channel, which occurs at the interphase between an adjacent pair of liver cells in a plate. The walls of the canaliculus are formed by the plasma membrane of the opposite hepatocytes. These canaliculi drain bile, produced by hepatocytes, toward the bile duct at the periphery of the lobule, in the portal triad.

A polygonal hepatic cell is thus exposed on its two or three sides to which blood flows toward the central vein. The same hepatic cell also forms bile canaliculi on its 3 or 4 remaining sides.

Liver Remember:

The structural and functional unit of the liver is the “hepatic lobule” which looks somewhat similar to a hexagon. There is no well-defined separation between adjacent lobules and at the corners (angles) of the hexagon (lobule) there are small triangular areas that contain “portal triads.” In the centre of each hepatic lobule is a central vein.

Three Different Types of Liver Lobules

The following three kinds of structural and functional lobules are described in

1. Classical liver lobule:
   • It has a central vein located in the centre of the lobule and portal triads at the edges of the cross-sectioned lobule.
   • The blood flows from the periphery to cen¬tre and secretion (bile) from the centre toward the periphery (portal triad).
2.  Portal lobule:
   • It is a triangular area of the liver parenchyma around each portal triad. It includes the portions of three neighbouring classical lobules. In this kind of lobule, the portal triad is in the central position and central vein at the edges of the cross-sectioned lobule.
   • This lobule indicates that blood supply to liver parenchyma goes from the centre to the periphery and bile secretion drains into the central duct.
3. Liver acinus:
   • This is the most commonly accepted structural and functional lobule. Liver acinus is elliptical and includes portions of two neighbouring classical lobules.
   • In the centre of the acinus are terminal branches of the hepatic arteriole and portal venule extending laterally from the portal triad, and the central vein at each pole of the cross-sectional structure.
   • It is considered that an acinus has three zones, i.e., zones 1, 2 and 3.
   • Zone 1 is close to blood vessels and zone 3 is close to a central vein.
   • Thus, zone 1 is supplied with blood that is most oxygenated and rich in nutrients and zone 3 gets the least.
   • The cell degeneration as seen in toxic damage to the liver is first observed in the central part (zone 1) as it is exposed to toxin before zone 3, while degeneration secondary to hypoxia is first observed in zone 3.

Lobules liver Remember:

Three different types of lobules are described in the liver, i.e., classical lobule, portal lobule and hepatic acinus. The classical hepatic lobule is a roughly hexagonal mass of tissue. The portal lobule connects three central veins and surrounds a portal triad. The liver acinus is the smallest functional unit of hepatic parenchyma.

Hepatic Sinusoids:

The sinusoids are between the hepatic laminae (plates) and follow their branching and anastomoses Their calibre is larger than capillaries (9-12 pm). Sinusoids are lined by two kinds of cells, i.e., endothelial cells and phagocytic (Kupffer) cells.

• The lining of endothelial cells is not continuous; gaps are seen between neighbouring endothelial cells. The endothelial cells have fenestrations that are not covered by the diaphragm.
• The basal lamina surrounding the sinusoids is either incomplete or absent. The sinusoidal epithelium is separated from the underlying hepatocytes by a small space, called the space of Disse (perisinusoidal space).
• The particulate matter less than 0.5 m in diameter may pass through the lumen of the sinusoid into space of the Disse

The phagocytic Kupffer cells lie by the side of endothelial cells and send cytoplasmic processes (filopodia) between adjacent endothelial cells. They do not form junctions with the neighbouring endothelial cells. Kupffer cells may send their cytoplasmic processes in the space of Disse through fenestrations or the gap between two endothelial cells.

Many microvilli project in the space of Disse from the basal surface of the hepatocytes. They increase the sur¬face area for the exchange of material between blood and liver cells. Blood plasma freely enters the Space of Disse and directly bathes the surface of the hepatic cells.

Ito cells (hepatic stellate cells):

Ito cells (hepatic stellate cells are another type of cells found in perisinusoidal spaces. These cells are involved in the storage of vitamin A and lipids. In chronic inflammation or cirrhosis, they differentiate into cells with characteristics of myofibroblasts, which produce collagen fibres resulting in liver fibrosis.

Hepatic Sinusoids Remember:

Hepatic sinusoids are vascular channels between the plates of hepatocytes. Sinusoids are lined by endothelial and phagocytic (Kupffer) cells. Gaps are seen between neighbouring endothelial cells. The endothelial cells have fenestrations that are not covered by the diaphragm. Perisinusoidal space (space of Disse) is seen between sinusoidal endothelium and hepatocytes.

2. Hepatocytes (Liver Cells)

Each liver cell is polygonal in shape possessing a relatively large nucleus (may be binucleated) and a single nucleolus. Hepatocytes have granular acidophilic cytoplasm but also contain basophilic bodies.

• Hepatocytes constitute about 80% of liver volume. Their life span is of about 5 months and are capable of regeneration.
• The polyhedral liver cells may have 5-12 sides and are about 20-30 cm in width. These cells form hepatic cords, which may branch and anastomose frequently.
• Some sides of the cells are exposed to the sinusoids, and the sides which are not exposed to sinusoids show infolding between adjacent cells to form bile canaliculi. The bile canaliculi form a network within the cell plates.

3. Electron Microscopic Structure of Liver Cells

The electron micrograph of liver cells shows the presence of numerous oval mitochondria with leaf-like cristae. Hepatocytes contain rough and smooth endoplasmic reticulum, free ribosomes, and many small Golgi complexes located near the bile canaliculi. There are many lysosomes and peroxisomes. Peroxisomes are involved in the detoxification of alcohol. Glycogen granules and lipid vacuoles are also seen.

4. Blood Circulation

The hepatic artery and portal vein after entering the porta hepatitis divide repeatedly to lie between hepatic lobules.

• The blood vessels present in portal triads are called interlobular vessels.
• The interlobular vessels of portal triads branch into vessels, which lie at the periphery of the lobules (between the lobules).
• These vessels are called distributing vessels.
• The distributing vessels are branches of the portal vein (which brings deoxygenated blood along with J-absorbed products of digestion) and the hepatic artery (which brings arterial blood) rich in oxygen.
• The distributing vessels send branches to liver sinusoids.
• The flow of mixed blood (arterial and venous) in sinusoids is from the periphery toward the central vein. The central veins join to form hepatic veins, which ultimately drain into the inferior vena cava.

Liver Functions 

• The liver has several functions, most of which are performed by hepatocytes.
• Liver cells produce not only exocrine secretion bile but also perform many endocrine functions.
• It modifies the structure and functions of many hormones.
• The liver produces most of the circulating plasma proteins.
• It is involved in many metabolic pathways, storage of vitamins and detoxification of toxins.
• The liver has several functions, most of which are performed by hepatocytes.
• Liver cells produce not only exocrine secretion bile but also perform many endocrine functions.
• It modifies the structure and functions of many hormones. The liver produces most of the circulating plasma proteins.
• It is involved in many metabolic pathways, storage of vitamins and detoxification of toxins.

Liver Clinical Application

Cirrhosis of the Liver:

• The function of liver cells is to detoxify drugs and toxic chemicals including alcohol.
• Those people who consume alcohol regularly for many years may develop a disease of the liver called cirrhosis.
• In this disease, there occurs the necrosis (death) of liver cells. These dead cells are replaced by fibrous tissue.
• The patient gradually becomes weak and develops jaundice due to the obstruction in the flow of bile.
• The other agents, which may cause cirrhosis are drugs, chemicals, hepatitis virus and autoimmune liver disease.
• Chronic viral hepatitis [^(B or C type) may also lead to cancer of the liver.

Liver Regeneration

The liver has high regenerative power. It can regenerate after toxic damage and even if a portion of it is excised.

Gallbladder

The gall bladder is a temporary storehouse of bile and concentrates it by water reabsorption.

It consists of the following layers:

1. Mucosa
2. Fibromuscular layer
3. Adventitia/Serosa

1. Mucosa:

It consists of simple tall columnar epithelium and lamina propria of loose connective tissue.

• The mucosal glands and muscularis mucosae are absent.
• The mucosa is thrown into small folds when the gall blad¬der is empty. The gall bladder epithelial cells have a basally placed ovoid nucleus and faintly stained eosinophilic cytoplasm.
• These cells have many small microvilli on their apical surface.
• These cells are highly involved in the absorption of water from stored bile. Lamina propria is present but submucosa is absent.

2. Fibromuscular Layer:

• This layer is composed of randomly arranged smooth muscle fibres.
• In between muscle fibres is dense connective tissue that is rich in elastic fibres.

3. Adventitia/Serosa:

• There is a layer of dense connective tissue outside the muscle layer, which contains blood vessels, nerves and lymphatics.
• This layer is called adventitia. On its inferior surface gall bladder is covered by se-rosa, rest of it is covered by adventitia.

 Gall bladder Remember:

The muscularis mucosae and submucosa are absent in the wall of the gall bladder. The release of bile from the gall bladder is controlled by cholecystokinin and vagal stimulation.

Gallbladder Clinical Application

Gallstones and Jaundice:

• Sometimes due to the presence of a higher concentration of bile acids in bile, there may occur the formation of stones in the gall bladder.
• If a gallstone obstructs the bile duct, it causes jaundice.
• Jaundice is a disease where there is the presence of an increased amount of bile pigments in the blood.

Pancreas

The pancreas is an accessory gland of digestion. This lies wholly outside the alimentary tract and is connected to it (duodenum) by an excretory’ duct(s). The pancreas is a mixed gland, i.e., it consists of an exocrine and an endocrine portion.

• The exocrine pancreas secretes pancreatic juice that helps in the digestion of carbohydrates, proteins and fats, while the endocrine pancreas secretes hormones, which regulate the metabolism of carbohydrates.
• The exocrine pancreas shows a similar structural organization as that of salivary glands.
• The secretory units of acini of the exocrine pancreas are tubuloacinar in shape and resemble a bunch of grapes where stems are comparable to the duct system and secretory acini are comparable to grapes.
• The endocrine units are called the islets of Langerhans. These are clusters of pale staining cells situated between the exocrine acini.

Pancreas Remember:

The pancreas is a mixed gland, i.e., exocrine and endocrine. The exocrine pancreas produces serous digestive juices and the endocrine pancreas produces hormones.

Histology of Exocrine Pancreas

The pancreas is covered with a very thin layer of loose con¬nective tissue capsule. Thin septa arise from this to divide the gland into many small lobules. These lobules are not very distinct. The interlobular connective tissue contains large ducts, blood vessels, and nerve fibres. The interlobular loose connective tissue surrounds the acini, small ducts and islets of Langerhans

1. Pancreatic Acini

The pancreatic acini are serous. Their shape is either round or slightly elongated.

• These acini are lined by pyramidal cells and have small lumen. The intercalated duct begins within the acini (see below).
• The acinar cells show all the features of a serous-secreting cell. These cells have centrally placed round nuclei.
• The intranuclear region is intensely basophilic (stains with haematoxylin) because it contains a rough endoplasmic reticulum and many free ribosomes.
• The supranuclear region is filled with secretory granules called zymogen granules The apical portion takes eosinophilic staining or may stain light basophilic. These secretory granules contain the precursors of several digestive enzymes.
• These enzymes are amylase, lipase, ribonuclease, deoxyribonuclease, trypsinogen, chemo-trypsinogen, etc. The release of these enzymes is controlled by cholecystokinin and acetylcholine.
• The cholecystokinin is liberated by the small intestine (mostly duodenum), which acts on the receptors of pancreatic acinar cells.
• Similarly, stimulation of parasympathetic nerves secrete acetylcholine, which facilitates the secretion of enzymes from pancreatic acini.

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1. Islets of Langerhans
2. Pancreatic acini
3. Pancreatic lobule
4. Blood vessels
5. Interlobular duct

Islets of Langerhans Present Acini And Intrabular Ducts:

Pancreatic Remember:

The pancreatic acini are lined by pyramidal cells and have small lumen. They are serious in nature and manufacture and release digestive enzymes. Pancreatic exocrine secretion is controlled by hormones (cholecystokinin) and nervous system (acetylcholine).

2. Ducts

The pancreas, like salivary glands, has an extensive duct system, i.e., intralobular (intercalated), interlobular and main duct.

• The intralobular ducts are very small in diameter and lined by squamous to very low simple cuboidal epithelium.
• An intercalated duct commonly begins within the acinus. Therefore, the ends of intercalated ducts are surrounded by acinar cells.
• Cells of intercalated ducts add bicar¬bonate and water to the exocrine secretion. The acinar lumen may show pale staining cells of the intercalated duct. These cells are called centroacinar cells. There are no striated ducts in the pancreas.
• The intercalated ducts are short and open into ’ intralobular collecting ducts’, which are lined by cuboidal or low columnar epithelium.
• The interlobular ducts are lined with simple columnar epithelium and lie in connective tissue septa.
• The main duct is lined with tall columnar cells with occasional goblet cells.

Duct Remember:

The centroacinar cells are part of the intercalated duct. Cells of intercalated ducts add bicarbonate and water to the exocrine secretion.

Histology of Endocrine Pancreas

The endocrine component of the pancreas is in the form of small groups of cells (“islands”), which are scattered among the acini of the exocrine pancreas. These small groups of cells are called “islets of Langerhans.”

• The islets are lightly stained with H&E and thus can be easily differentiated from acini, which are darkly stained.
• The cells of islets are arranged as anastomosing plates or cords and permeated by a rich network of fenestrated capillaries. They pour their secretions directly into blood capillaries.
• The islets contain mainly four kinds of cells, which can be distinguished by special stains, but not by H&E.

These cells are designated as:

• α (alpha) cells: These are 20% of the total population of islet cells and secrete glucagon. Glucagon acts antagonistically to insulin.
• β (beta) cells: These are 70% of the total population and secrete insulin, which promotes the uptake of glucose.
• δ (delta) cells: These are 5% and secrete somatostatin, which suppresses the release of insulin and glucagon.
• PP cells: These cells secrete pancreatic polypeptides, which regulate acinar cell secretion (PP = protein polypeptide).

Pancreas Clinical Application

• Diabetes: Diabetes is caused by to impaired function of beta cells of islets of Langerhans. In this condition, these cells are unable to produce the required amount of insulin.
  • A person suffering from diabetes has high blood levels of glucose. The glucose may also get excreted through urine. The disease if remains untreated may lead to atherosclerosis and partial blindness from degenerative changes in the retina.
  • Diabetes occurs in two forms, i.e., type 1 and type 2:
  • In type 1 the f3 cell of islets are destroyed before the age of 15 years. These patients are dependent on the injection of insulin as no insulin is produced by islets.
  • Type 2 (non-insulin-dependent diabetes) usually occurs after 40 years of age and in.

General Histology Of The Alimentary Canal

The alimentary canal, from the oesophagus to the anal canal, may be identified by its tubular nature and also by the division of its wall into four layers.

These layers from deep to superficial are :

1. Mucosa
2. Submucosa
3. Muscle layer
4. Serosa

1. Mucosa

This is the innermost layer of the alimentary canal and com-prises lining epithelium, lamina propria and muscularis mucosae.

• Epithelium: Different types of epithelium line different parts of the alimentary canal, i.e., the oesophagus and anal canal are lined by protective epithelium (stratified squamous); the intestine and stomach are lined by simple columnar, which is absorptive and secretory.
• Lamina propria: This is a layer of loose connective tis¬sue, which supports the epithelium. It contains the blood and lymphatic vessels through which nutrients are absorbed.
  • Lamina propria also accommodates glands like gastric glands in the stomach and crypts of Lieberkuhn (intestinal glands) in the mucosa of the intestine. These glands develop from the invagination of luminal epithelium.
  • The lamina propria also contains “mucosa-associated lymphoid tissue.” i.e.. lymphocytes and macrophages.
  • These lymphocytes and macrophages are defensive as the alimentary canal is subjected to the entry of foreign substances like bacteria and other microbes.
  • These lymphoid tissues may be in the form of lymphatic nodules (as in the appendix) or the form of diffuse tissue,
• Muscularis mucosae:
• This consists of a thin layer of smooth muscle cells. These are arranged as inner circular and outer longitudinal layers. The muscularis mucosae can change the shape of the mucosa, which helps in absorption and secretion.

Lamina propria Remember:

Lamina propria contains the blood and lymphatic vessels through which nutrients are absorbed. It also contains glands (intestinal glands) and lymphoid tissue. The secretory function of mucosa provides lubrication and delivers digestive enzymes and hormones. Lymphoid tissues are defensive and protect the intestine from foreign substances.

2. Submucosa:

It consists of moderately dense, irregular connective tissue rich in collagen and elastic fibres.

• The submucosa contains blood vessels, lymphatic vessels, nerves and Meissner’s plexus.
• In some parts of the alimentary tract (oesophagus and duodenum), the submucosa contains glands that pour their secretion into the lumen of the gut through ducts.
• This layer may also contain scattered lymphoid nodules, particularly in the large intestine.

3. Muscle Layer:

In most of the parts of the alimentary tract, this layer is made up of an outer sheet of longitudinally arranged smooth muscle fibres and an inner sheet of circularly arranged fibres.

• This layer also contains myenteric plexus (Auerbach’s plexus) between circular and longitudinal sheets of muscle fibres.
• This plexus mostly controls the motility of the tract.

4. Serosa Adventitia:

The serosa is the superficial layer on the parts of the alimentary tract present in the abdominal cavity.

• It is a visceral peritoneum composed of connective tissue and simple squamous epithelium.
• The oesophagus part of the alimentary tract, which is outside the abdominal cavity, has a superficial layer called adventitia that consists of areolar connective tissue.

 Serosa Remember:

Contraction of the muscle layer mixes and propels the contents of the digestive tract. The serosa or adventitia is the outermost layer of the alimentary canal.

Oesophagus

The oesophagus is a straight muscular tube extending from the pharynx in the neck to the stomach in the abdomen. Most of it lies in the thoracic cavity.

Its wall is made up of four layers:

1. Mucosa
2. Submucosa
3. Muscle layer
4. Serosa

1. Mucosa

• Epithelium: It consists of thick non-keratinized strati¬fied squamous epithelium.
• Lamina propria: It consists of a thin layer of loose con¬nective tissue
• Muscularis mucosae: It is unusual in two respects; firstly, it is thicker compared to other parts of the alimentary canal. Secondly, it is single-layered and formed by longitudi¬nally running smooth muscle fibres. Sometimes, the mucosa of the oesophagus may contain mucous glands in its uppermost (near the laryngopharynx) and lower (near the stomach) regions.

2. Submucosa

It is a wide layer of irregular, moderately dense connective tissue composed of bundles of collagen and elastic fibres.

• Due to the presence of elastic fibres, the submucosa is thrown into folds.
• Hence, the lumen of the oesophagus appears star-shaped. The submucosa contains blood vessels and branched tubuloalveolar mucous glands.
• Ducts arising from these glands run through lamina propria to open into the lumen of the oesophagus.

3. Muscle Layer

The muscle layer is different in different parts of the oesophagus.

• In the upper third portion, the muscle is skeletal.  It consists of both skeletal and smooth muscles in the middle portion.
• In the lower third, it consists of purely smooth muscle.

These muscles are arranged in two layers, i.e… an outer longitudinal and an inner circular. A well-formed myenteric plexus of nerve fibres and ganglion cells exists between the two muscle layers. It controls the peristaltic movements.

4. Serosa/Adventitia

The superficial layer, adventitia, consists of loose areolar connective tissue, which merges with the connective tissue of surrounding structures. The adventitia surrounds most of the oesophagus, except for the lowest 1 inch where it is covered by serosa.

Oesophagus Functions

• The oesophagus has neither digestive nor absorptive functions.
• It is involved in the transport of food and water from phar¬ynx to the stomach. The bolus of the food travels in the oesophagus at the rate of 50 mm per second.
• It secretes mucus that lubricates the lumen of the oesopha¬gus to facilitate the transport of food.

Oesophagus Remember:

The glands of the mucosa and submucosa of the oesophagus secrete the mucus to facilitate the transport of food and protect the mucosa of the oesophagus. The muscle layer in the upper part of the oesophagus consists of skeletal muscle, while in the lower part it consists of smooth muscle. However, in the intermediate part, it is mixed.

Stomach

Based on histological structure, the stomach is divided into three distinct regions

1. Cardiac region: This part of the stomach is about 2-3 cm wide at the junction of the oesophagus.
2. Fundic region (or body): This region consists of fun¬dus and body.
3. Pyloric region: This region connects the stomach to the duodenum

In an empty stomach, the mucosa and submucosa are thrown into longitudinal folds called rugae. These rugae disappear when the stomach is distended with food. The epithelial lining of gastric mucosa contains many depressions called gastric pits.

From the bottom of each gastric pit, several tubular gastric glands extend into the lamina propria A section through the wall of the stomach shows the usual four layers, i.e., mucosa, submucosa, muscle layer and serosa

1. Cardiac Region

1. Mucosa:

• The epithelial lining, at the cardio-oesophageal junction, changes from stratified squamous epithelium to simple columnar epithelium. The columnar epithelium of the cardiac region shows basal, oval nuclei.
• These cells are involved in the secretion of mucus and arc called mucous surface cells.
• The goblet cells are not present in this epithelium. The lamina propria contains small tubular glands that open in gastric pits.
• These glands are lightly stained with ll&E and arc called mucus-secreting cardiac glands. The muscularis mucosae contain smooth muscle fibres arranged in two layers.

2. Submucosa:

The submucosa is a broad layer of connective tissue. It consists of blood vessels and nerve plexus (Meissner’s plexus).

3. Muscle Layer:

It is composed of three thickened layers of smooth muscle bundles inner oblique, middle circular and outer longitudinal. The inner oblique layer is not always apparent. The myenteric plexus may be seen in connective tissue between muscle layers.

4. Serosa:

Serosa is our most covering formed by simple squamous epithelium resting on a layer of connective tissue.

2. Fundic or Body Region

Following lour layers mo observed in this region.

1. Mucosa:

Lining Epithelium:

• The epithelium, which lines the surface and the gastric pits, is a simple columnar mucous epithelium.
• These cells are involved in the secretion of mucus. The mucus protects the epithelial lining from damage due to the presence of acid in the stomach.
• These cells are replaced every few days (3 5) with the proliferating cells of gastric pits.

Lamina propria:

Simple tubular glands arc present in lamina propria, which extend from the bottom of the gastric pit to the muscularis mucosae. They are called gastric glands or fundic glands and several may open at the bottom of a gastric pit. The isthmus is a small segment between the gastric pit and the fundic gland.

The cells of the isthmus divide and migrate upwards and downwards. These cells give rise to the cells of the surface epithelium and various cells of the gastric gland. In H&E sections.

The following types of cells can be identified in fundic glands:

• Mucous neck cells:
  • These cells are located just below the gastric pit. They are columnar and have mucinogen granules in apical cytoplasm, while nuclei arc basally situated.
  • They produce mucus of a different nature than that of surface epithelium.
  • They produce soluble mucus compared to insoluble mucus produced by surface mucous cells. The parietal cells are seen located with mucous neck cells.
  • Mucous neck cells also contain few regenerative (stem) cells. These cells proliferate to replace all of the specialized cells lining the gastric gland, gastric pit and surface. The mucous neck cells are replaced every 5-7 days.
• Parietal or oxyntic cells:
  • They produce HCl and intrinsic factors. These cells are mostly found in the upper half of gastric glands.
  • The parietal cells are large, rounded or pyramidal. These cells are wedged against the basement membrane.
  • In H&E preparation, they are stained dark pink. The electron micrographs, show the presence of a deep infolding of the apical membrane forming an “intracellular canaliculus” into which many microvilli. The cytoplasm contains tubulovesicular structures under the microvilli and many mitochondria.
  • The tubule-vesicular structures are involved in HCI secretion.
  • The synthesis of HCl takes place by the combination of Cl ions inside the intracellular canaliculi (outside cell). Both H⁺ and Cl^– ions are secreted by parietal cells. The life span of parietal cells is 150-200 days.

HCI Remember:

HCI is produced outside the parietal cell, be, in the lumen of the intercellular canaliculus.

• Chief or zymogenic cells:
  • Most of these cells are located in the lower third of gastric glands.
  • They usually take basophilic stains and thus are easily differentiated from parietal cells, which are strongly eosinophilic.
  • The chief cells contain a rough endoplasmic reticulum near the base, secretory granules near their apex and a small Golgi apparatus.
  • These cells are typical protein-secreting cells and secrete pepsinogen, which is converted to a proteolytic enzyme pepsin in an acid environment.

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• Enteroendocrine and APUD cells:
  • These cells are located in the basal portion of gastric glands.
  • In the H&E section, the cells appear unstained. They contain secretory granules, which stain only in special preparations.
  • They are thought to produce serotonin, histamine and gastrin.
  • As these cells are endocrine cells, they release their products into the blood vessels.

Muscularis mucosae:

It consists of two thin layers of smooth muscles, i.e., outer longitudinal and inner circular.

Lamina propria Remember:

Lamina propria of the fundic or body region contains fundic (gastric) glands, which secrete gastric juice of the stom¬ach. Gastric juice contains hydrochloric acid (HCI) and intrinsic factors, pepsin and mucus. Parietal cells produce HCI and gastric intrinsic factor, while chief cells produce pepsinogen, reninin and gastric lipase. Mucus neck cells produce mucus.

2. Submucosa:

The submucosa is the same as described under general histol¬ogy of the alimentary canal.

3. Muscle Layer:

It has three layers of smooth muscle, i.e., in the outermost layer muscle fibres are oriented longitudinally, in the middle layer Fibres are circular and in the inner layer are obliquely arranged. The outer longitudinal layer is not very complete.

4. Serosa:

It is the outermost layer of the stomach and consists of loose connective tissue covered by mesothelium.

Fundic Or Body region Functions

• Mixing, partial digestion and storage of food.
• Production of gastric juice, i.e., pepsin, HC1, renin, in¬trinsic factor, hormones and mucus.
• Absorption of water and salt (slight). Alcohol and aspi¬rin enter the lamina propria by damaging surface epithelium.

3. Pyloric Region

1. Mucosa:

• The surface epithelium is the same as present in the fundic part of the stomach. The pyloric glands occupy the lamina propria (Fig. 14.8 A and B).
• The gastric pits of these glands are deeper and extend through half the thickness of the mucosa. These glands are short, tortuous and branched. They are lined by one-cell
• Type, which is similar to mucous neck cells. They produce mucus and gastrin. Muscularis mucosae is same as in fundic part.

2. Muscle Layer: The circular muscle is much thickened and forms a pyloric sphincter.

3. Submucosa and Serosa: Same as in the fundic part.

Pyloric Region Clinical Application

Pernicious Anaemia:

The parietal cells also serve as the source of intrinsic factors. The intrinsic factor is a must to absorb vitamin Br from the small intestine. In the absence of parietal cells (due to disease or surgery), the vitamin Bn is not absorbed, which leads to a condition known as pernicious anaemia. Parietal cells may also decrease in old age. The pernicious anaemia is treated by giving injections of vitamin B12.

Small Intestine

The small intestine is about 5 m in length and consists of three parts, i.e., duodenum (about 12 cm in length), jejunum (2 m) and ileum (3 m). This long tube extends from the stomach to the colon and is highly coiled. The major function of the small intestine is digestion and absorption. Most of the nutrients are absorbed by the small intestine.

 Intestine Remember:

The absorptive surface area of the intestine is increased by the formation of plicae circularis, villi and microvilli. The plicae circularis (valves of Kerckring) are permanent mucosal folds. These structures do not disappear on distension as they contain the core of the submucosa. Besides increasing the absorptive surface area, they also decrease the velocity of movement of contents.

1. Duodenum

It consists of four layers, i.e.,

1. Mucosa
2. Submucosa
3. Muscle layer and
4. Serosa/adventitia.

1. Mucosa:

• In the duodenum, the mucosa and submucosa are thrown into circular folds called plicae circularis. These mucosal folds are permanent structures and do not disappear on distension. This is because they contain the core of submucosa.
• The function of plicae circularis is to slow the passage of contents and to increase the surface area of mucosa.
• The surface area of the mucosa is further increased because of the presence of mucosal villi. The plicae are covered with villi. Villi are fingerlike mucosal projections about 0.5 mm in length.
• The core of each villus is formed by loose connective tissue of lamina propria containing fenestrated capillaries, smooth muscle fibres and lymphatics (blind-end lacteals).
• The surface of the villi is covered by epithelium consisting predominantly of columnar cells with striated borders (microvilli). In between the columnar cells, a few goblet cells are also present.

Mucosa Remember: 

• The mucosa of the intestine consists of villi, intestinal glands along with lamina propria, lymphocytic collections and muscularis mucosae.
• In between the bases of two intestinal villi, the epithelium is invaginated in lamina propria to form intestinal glands (crypts of Lieberkuhn). These glands are short tubular glands that open into the lumen of the intestine at the base of the intervillous space. These glands are lined by columnar cells, goblet cells, Paneth cells and enteroendocrine cells.
• The lamina propria, in between tubular intestinal glands, consists of loose connective tissue, reticular cells and diffuse lymphoid tissue. Occasionally, lamina propria may also contain submucosal Brunner’s glands. The muscularis mucosae sends smooth muscle fibres towards the core of the villi.

2. Submucosa:

The submucosa is almost completely occupied by highly branched, tubuloacinar duodenal glands. Brunner’s glands. The ducts of these glands pass through muscularis mucosae and open into the lumen of the duodenum. The acini of duodenal glands secrete mucus, hence taking light stain.

• These acini are lined with cuboidal or low columnar cells.
• Duodenal glands secrete alkaline mucus with high concentrations of bicarbonates that protect the duodenal mucosa from acid secreted by the stomach.
• Brunner’s gland also secretes “human epidermal growth factor,” which increases the mitotic activity of epidermal cells.
• This factor also inhibits the secretion of HCl.

3. Muscular Layer: It is made up of outer longitudinal and inner circular layers of smooth muscle.

4. Serosa/Adventitia: As most of the duodenum is retroperitoneal, some parts of its surface may show serosa. Otherwise, it is covered by adventitia.

Brunner’s gland Remember:

Brunner’s gland secretes “human epidermal growth factor” (which increases the mitotic activity of epidermal cells) besides producing mucous and alkaline fluid to neutralize the acidic chyme.

2. Jejunum

It also consists of four layers.

1. Mucosa:

Similar to the duodenum, the mucosa and submucosa of the jejunum are also thrown into permanent circular folds (plicae circularis), which bear tongue-shaped villi of different heights.

• Each villus is covered with tall columnar cells having a striated border. The core of each villus is formed by lamina propria containing diffuse lymphatic tissue, blood vessels, smooth muscle fibres and central lacteal.
• The crypts of Lieberkuhn (intestinal glands) are present in lamina propria below the bases of villi.
• These glands contain four different types of cells, i.e., absorptive columnar cells, goblet cells, enteroendocrine cells and Paneth cells
• Paneth cells play an important role in controlling the bacterial flora of the small intestine by producing antibacterial agents lysozyme and defensin.

Following are the main hormones secreted by gastric and intestinal enteroendocrine cells glucagon, serotonin, endorphin, histamine, gastrin, somatostatin, secretin, cholecystokinin (CCK), gastric inhibitor.’ peptide (GIP), noradrenaline and vasoactive intestinal peptide (VIP). The muscularis mucosae are in the usual two layers.

2. Submucosa

It is made up of connective tissue, blood vessels, nerve plexus (Meissner’s plexus) and lymphatics. Although no Peyer’s patches are seen, occasionally a lymph nodule may occur. No Brunner’s glands are seen.

3. Muscular Layer

It is the same as in the duodenum.

4. Serosa

It covers the jejunum to form an outermost layer.

Jejunum Remember:

Crypts of Liberkuhn or intestinal glands: These are simple tubular or branched tubular glands present in lamina pro-pria below the bases of villi. They increase the surface area of the intestinal lining. These glands consist of surface absorptive cells, goblet cells, enteroendocrine and Paneth cells.

Enterocytes are tall columnar and have elongated nuclei situated at the base. They are absorptive cells and transport water and substances from the lumen of the Intestine to the blood capillaries. They are also secretory cells, producing enzymes, which help In digestion and absorption.

3. Ileum

The ileum also has the usual four layers in its wall, i.e., mucosa, submucosa, muscle layer and serosa.

1. Mucosa

The epithelial lining of villi consists of the same absorptive columnar cells as present in the jejunum. The villi arc is few, short and finger-like. Lamina propria contains intestinal glands and aggregation of lymphatic nodules called Peyer’s patches. The number of lymphatic nodules increases in the distal ileum where they are covered with rudimentary villi.

In the ileum where Peyer’s patches are much larger they extend into the submucosa after disrupting the museularis mucosae. The muscular mucosae is thin or absent whereas Peyer’s patches are large.

Submucosa, Muscle Layer and Serosa

These layers are the same as in the jejunum.

Peyer’s Patches and “M” Cells

The mucosa intestine is exposed to toxins and microorganisms. To protect the gut from this invasion, there is the presence of lymphocytes, plasma cells and macrophages in the connective tissue of lamina propria. In the terminal portion of the ileum, there are aggregations of lymphatic nodules (Peyer’s patches).

• Overlying these lymphatic nodules, there are specialized “M” cells in between the columnar cells of the epithelium.
• These cells are broad and have few micro folds on their apical surface.
• The base of these cells is invaginated and occupied by lymphocytes and macrophages of underlying lymphoid tissue.
•  The formation of a deep recess in the M cell facilitates the lymphocytes to come in close contact with the bacteria and macro-molecules present on the apical surface of M cells.
• The M cells are capable of attracting bacteria and transporting their antigen across the cell to macrophages. The macrophages present the antigen to the surrounding lymphocytes.
• These lymphocytes then migrate to the lym¬phatic nodules in lamina propria. Mere, these lymphocytes then differentiate into plasma cells and produce the specific antibody.
• The antibodies (IgA) then pass from lamina propria to the surface of the epithelium through epithelial cells.
• Where (hey sil in the glycocalyx to neutralize toxins and microorganisms. Antibodies produced in lamina propria arc also re-circulated through the liver and gall bladder to the lumen of the intestine.

Ileum Remember:

M cells transport bacteria and other macromolecules from the lumen to cells of the immune system in Peyer’s patches and other large lymphocytic nodules. Thus, the M cell is considered an antigen-transporting cell

Large Intestine

The large intestine consists of the colon, rectum and anal canal.

Similar to the small intestine, the large intestine also has a mucosa, submucosa, muscle layer and serosa.

1. Colon

Mucosa:

The mucosal folds (plicae circularis) and villi are absent. Hence, the mucosal surface is smooth. The surface epithe¬lium principally consists of columnar cells and a few goblet cells. The columnar cells are absorptive and bear microvilli (striated border). These cells are involved in the absorption of lipids, water and salts.

• The lamina propria is occupied with tubular glands, which extend from surface to mus-cularis mucosae. The glands are straight and much longer than the glands of the small intestine.
• Glands are lined with few absorptive columnar cells and widely scattered enteroendocrine cells, but goblet cells now become Iho principal cells.
• Paneth cells may occur occasionally. In the lower third of the gland, the epithelium consists almost entirely of goblet cells. The lamina propria contains rinse lymphatic tissue and sometimes lymph nodules. The muscularis mucosae is typical.

Submucosa:

Its histological structure is typical.

Muscle Layer:

The outer longitudinal muscle layer is very thin. It is arranged in thick bands (taenia coli) only at three places. The inner circular layer of muscle is also thin compared to the small intestine.

Serosa:

It covers the transverse colon but parts of ascending and descending colon are covered by adventitia.

Colon Remember:

The mucosal surface of the colon is smooth as it has no villi or mucosal folds. The lining cells of mucosa consist predominantly of surface absorptive cells, which are involved in the absorption of lipids, water and salts. The number of goblet cells increases from the ascending colon to the sigmoid colon.

The lamina propria is occupied with tubular glands (crypts of Luberkhun), which extend from the surface to muscularis mucosae.

2. Rectum

Mucosa:

• The rectum is structurally similar to the colon. The intesti¬nal glands are straight like test tubes. The surface epithe¬lium and glands are lined predominantly with goblet cells.
• Entero-endocrine cells may be found, but Paneth cells are absent. Toward the termination of the rectum, the long intestinal glands decrease in length.
• The temporary longitudinal folds may be present in the upper rectum that has a core of submucosa.
• The permanent longitudinal folds of the rectum (rectal columns) appear in the lowermost rectum. The muscularis mucosae, in the lowermost rectum, appears as a thin layer.

Submucosa: It has a typical structure.

Muscle Layer:

In the rectum, the taenia coli are absent and a complete longi¬tudinal external muscle coat is present. The inner muscle coat is circular.

Serosa/Adventitia:

As the rectum is retroperitoneal, the serosa is present only

Functions of Colon and Rectum

• Absorption or remaining lipids, which are not absorbed by the small intestine.
• Absorption of water and salts that results in concentra¬tion of faeces.
• Secretion of mucus that facilitates the movement of intestinal contents.
• The mucus also protects the epithelium against abrasions by the concentrated faeces.

3. Anal Canal

Mucosa:

The mucosa of the anal canal has different histological structures in its upper, middle and lower parts.

• The upper part of the anal canal (the longitudinal anal columns) is covered by simple columnar epithelium similar to the rectum. There are few short intestinal glands in lamina propria, which gradually disappear as traced distally.
• The mucosa in the middle part is covered by stratified squamous non-keratinized epithelium.
• The uppermost portion of the middle part sometimes may show stratified cuboidal or columnar epithelium.
• The mucosa in the lowest part of the anal canal is covered with true skin and contains associated sebaceous and large apocrine glands. The muscularis mucosae disappear at the level of the middle part of the anal canal.
• The submucosa contains large thin-walled veins. These vessels are prime targets of varicosities or dilatations and are known as haemorrhoids.
• A thin layer of muscularis mucosa is present that disappears at the junction of the upper ar middle parts of the anal canal

Muscle Layer:

The circular muscle coat gets thickened to form an internal anal sphincter. The longitudinal muscle coat extends up to the middle part of the anal canal and then disappears.

Adventitia: It is the outermost layer.

Anal Canal Function

• Retention and elimination of wastes.

Diarrhoea Clinical Applications 

Diarrhoea is the production of stools that are more watery, more frequent or greater in volume than normal. Sometimes, diarrhoea is accompanied by abdominal pain, loss of appetite and vomiting.

• Severe diarrhoea can lead to dehydration and may be life-threatening, especially in infants.
• Diarrhoea, which starts all of a sudden is mostly caused by food poisoning. Diarrhoea may also be caused by viral or bacterial infections.
• Persistent diarrhoea may be due to chronic inflammation of the intestine due to disorders such as ulcerative colitis (inflammation of the large intestine) or malabsorption.
• Lactose intolerance (in this condition person can not digest the milk, i.e., lactose of milk) can also cause diarrhoea.
• If dehydration is treated properly by taking plenty of fluids then diarrhoea clears up within a day or two.
• If it lasts longer than 3-4 days, specific treatment is needed.

4. Appendix

The vermiform appendix is the appendage at the base of the caecum. It is the narrowest part of the large intestine. Its wall contains all four layers typical of the intestinal tract

Mucosa:

The epithelial lining of the mucosa is made up of absorptive 5 columnar cells, goblet cells and M cells.

• The M cells are antigen-transporting cells, which are present among the columnar cells of the epithelium overlying the lymphatic nodules.
• The lamina propria contains a few short intestinal glands. Enteroendocrine cells may be present in the intestinal glands, particularly those that secrete serotonin.
• The lamina propria is occupied with many large and small lymphatic nodules that may also extend into the submucosa.
• Lymphatic nodules with germinal centres can increase in size to such a degree that the narrow lumen of the appendix may be occluded.
• The muscularis mucosae are disrupted at places where lymphatic nodules extend into the submucosa.

Submucosa:

The submucosa is typical and may show the extension of lymphatic nodules.

Muscle Layer and Serosa:

The muscle layer consists of usual circular and longitudinal smooth muscle coats. The serosa forms the outermost layer covering the appendix completely.

• Innervation of Alimentary Canal The alimentary canal (from the oesophagus to the anus) is supplied by the enteric nervous system.
• This system consists of ganglia known as Meissner’s submucosal plexus and Auerbach’s myenteric plexus.
• These ganglia contain a large number of neurons (about 100 million). The enteric nervous system controls the mobility and secretion of the alimentary canal.
• Although the enteric nervous system is self-sufficient, its functions are modified by sympathetic and parasympathetic components of the autonomic nervous system.

Cancers of Intestine Clinical Application

Cancers of the intestine may arise from either surface epi- j thelium or glandular epithelium. Malignant tumours of the stomach and small intestine usually arise from surface 1 epithelial cells. However, in the case of the large intestine, malig¬nant tumours usually arise from the epithelium of intestinal glands. These tumours are called adenocarcinomas. Adenocarcinoma of the colon is the second most common cancer in humans.

Microscopic Structure of, mucosa of the gastrointestinal tract:

The Digestive System 1 Oral Cavity

The digestive system consists of two groups of organs

1. The gastrointestinal tract or alimentary canal: This is in the form of a tube that extends from the oral cavity to the anus. The parts of the gastrointestinal tract are: oral cavity, pharynx, oesophagus, stomach, small intestine, co¬ lon, rectum and anal canal.
2. The accessory digestive organs: These are teeth, tongue, salivary glands, liver, gall bladder and pancreas. In this chapter, we shall learn about the organs of the oral cavity and salivary glands pouring their secretion in the oral cavity.

Oral Cavity

In the oral cavity, food is broken into small pieces by the teeth, moistened and mixed with the secretions (which also contain hydrolytic enzymes) of salivary glands, for its passage through the oesophagus to the stomach

The oral cavity is lined by mucosa composed of stratified squamous epithelium, and a lamina propria of loose areolar connective tissue containing many mucus and serous secreting small glands. As this mucosa is subjected to friction of food, the epithelium at certain places in the oral cavity may show some degree of keratinization or it is para keratinized.

The para-keratinized epithelium is similar to the keratinized epithelium. Here, superficial cells do not lose their nuclei. The nuclei remain in these cells until cells are exfoliated

The lymphatic tissues (diffuse lymphatic tissue, nodules and tonsils) are present beneath the oral epithelium and provide a defence mechanism against infection as the oral cavity is the site of entry of foreign material.

The Lip

The lip consists of an external surface lined by skin, an internal surface lined by mucous membrane and the centrally placed skeletal muscle called orbicularis oris. The external and internal surfaces meet at the free border of the lip, which is also called as “red margin” of the lip.

• The skin ofthe lip is lined by the epidermis, which is keratinized stratified squamous epithelium. In the dermis, there is the presence of hair follicles, sweat glands and sebaceous glands.
• The inner surface flip is lined by non-keratinized stratified squamous epithelium. The lamina propria is present beneath the epithelium and contains labial mucous glands and blood vessels. The secretion of these glands keeps the oral mucosa moist.
• The free border (red margin) ofthe lip is the site of the mucocutaneous junction. It shows the transition ofthe epi¬ dermis ofthe skin to the epithelium of mucosa.
• Beneath the epithelium large number of blood vessels are present. which are responsible for the pink colour ofthe red margin of the lip

The lip Remember:

The external and internal, surfaces of the are lined by the skin and mucous membranes) respectively. These surfaces meet at the free border rof the margin or vermilion zone of the lip. The central core of the lip is formed.

Teeth

The teeth are accessory digestive organs located in the sockets of alveolar processes of the mandible and maxilla. The alveolar processes are covered by the gum. The root of the tooth is attached to the alveolar socket by periodontal ligaments, which consist of dense fibrous connective tissue

General Structure of a Tooth:

The parts of a typical tooth are. The crown is the part of the tooth above the level of the gum. The part of the tooth that lies embedded in the socket is called as root. The neck is the junction of the crown and root near the gum line

The central portion of a tooth is called as dentine. It is a calcified connective tissue that is harder than bone Dentine encloses a cavity called as pulp cavity. This cavity is filled with pulp, which consists of connective tissue containing blood vessels, nerves and lymphatic vessels. The pulp cavity continues down into the root as the root canal.

Each root canal has an opening at its base, the apical foramen, through which blood vessels, lymphatic and nerve enter. The dentine of the crown is covered by enamel. Enamel is the hardest substance in the body and consists of calcium salts. The dentine ofthe root is covered by cementum, which is a bone-like tissue. The cementum attaches the root to the periodontal ligament

Detailed Structure of Tooth:

1. Dentine:

Dentine forms the wall of the root and roof of the pulp cavity. It is composed of 80% inorganic salts (crystals of hydroxyapatite) and 20% inorganic matter (type 1 collagen and other proteins). It is a hard material similar to bone.

• Dentine is characterized by dentinal tubules radiating outward from the pulp cavity to the outer wall of the tooth.
• These tubules, in a living state, are occupied by the processes of odontoblasts. These cells line the pulp cavity and are tall columnar.
• The apical portion of the cell gives rise to a slender odontoblast process. The dentinal tubules, containing processes of odontoblasts, are parallel to each other.
• The dentine is laid down in layers that lie parallel to the pulp cavity. The layer of newly formed dentine near the apical end of odontoblasts, which is yet to be mineralized, is called dentine.
• Formation of dentine is a continuous slow process, which occurs throughout life and the pulp cavity is gradually narrowed with advancing age.
• The layers of dentine may be separated by less mineralized tissue that forms the incremental lines of Von Ebner. These lines reflect the cyclic pattern of cellular activity during the formation of dentine.

Dentine Remember:

Dentine consists of alcified tubules which are occupied by the processes of odontoblasts. the dentine of the root is covered by cementum, which is a bone-like tissue.

2. Enamel:

Enamel is made up of 99% of inorganic salts (hydroxyapatite crystals). Hence, it is considered to be the hardest substance in the body.

• Histologically, the enamel consists of enamel rods or prisms that radiate from the dentin enamel junction towards the enamel surface.
• The enamel rods are bound together by a thin layer of organic matrix called the prismatic rod sheath
• Enamel is an extracellular product of enamel organ cells. It is produced by a layer of columnar cells called ameloblasts, which covers the crown as an epithelial membrane.
• Following completion of enamel deposition (before the eruption) the ameloblasts wear off and never return.
• Thus no further deposition of enamel is possible. Therefore, this layer of ameloblasts is not present in mature teeth. Enamel is produced in waves, producing growth lines.
• These lines are at a right angle to the direction ofthe enamel rods.
• These lines are called contour Lines of Retzius and reflect the wave of enamel formation. Any erosion in enamel (caries) must be repaired through filling.

Enamel Remember:

Enamel is composed of enamel rods, which are made up of calcium hydroxyapatite crystals. Enamel is the hardest substance in the body.

3. Cementum

The enamel at the neck (from the cementoenamel junction) to the apical pore

• The cementum is bone-like tissue. It is mineralized. The main organic component is collagen and proteoglycan.
• The cementum contains cementocytes in lacunae.
• Similar to an osteocyte, a cementocyte also contains many processes within canaliculi, which radiate from lacunae.
• Cementum is an avascular tissue in contrast to the bone which is vascular.
• The collagen bundles of the periodontal membrane are anchored to the cementum.

4. Periodontal Ligament:

The periodontal ligament connects the cementum to the bone of the alveolar socket.

• It is made up of both loose and dense connective tissue.
• The dense connective tissue is found in the bulk of the periodontal ligament.
• The loose connective tissue provides passage to the blood vessels and nerves.
• Besides providing attachment and support to the tooth the periodontal ligament also helps in bone remodelling during the eruption of teeth

5. Dental Pulp:

The dental pulp is present in the pulp cavity, which is bounded by mineralized dentine. The pulp on its periphery has a layer of odontoblasts.

• The central portion of the pulp consists of fibroblasts, macrophages, mast cells, collagen fibrils and a large amount of ground substance.
• The neurovascular bundles form a network in the crown portion of the pulp, just beneath the layer of odontoblasts.
• The nerve fibres forming this network contact the cell body of odontoblasts and may also travel in dentinal tubules.
• Because of this reason, dentine is highly sensitive to pain.
• The capillary loops that form the network also enter the layer of odontoblasts.

Tooth Clinical Application

• Dental Caries: If the hygiene of the oral cavity is not maintained properly, the bacteria present in the oral cavity may destroy the enamel and dentine.
  • Bacteria when act on sugar present In the oral cavity produce acid. This acid gradually de-mineralizes the enamel and dentine leading to their destruction.
  • The resulting condition is called dental caries. If infection is not controlled, it may reach up to the pulp cavity.
  • The infection of the pulp is painful as it has sensory nerve endings
• Orthodontic Treatment: With the help of orthodontic treatment, the disposition of teeth can be gradually changed.
  • As the periodontal ligament is plastic, it allows the change in the disposition of teeth in the mouth.
  • Similarly, cementum has lower metabolic activity because it is not supplied by blood vessels.
  • Both the above facts help in the movement of teeth by orthodontic appliances.

Tongue

The tongue is an accessory digestive organ composed of skeletal muscle covered with mucous membranes. The lining mucosa consists of stratified squamous epithelium and a lamina propria.

An inverted V-shaped groove, the sulcus terminalis, divides the dorsal aspect of the tongue into anterior 2/3 (body of the tongue) and posterior 1/3 (the root of the tongue) The dorsal aspect of the root of the tongue (posterior 1/3) contains many oval or rounded elevations, which are due to the lingual tonsils.

These elevations may contain lymph nodules and may show the presence of germinal centres in. Elsewhere, where lymph nodules are not present, the mucosa shows the general properties of lining mucosa. The lingual salivary glands of the posterior 1/3 of the tongue are mostly mucous and are located in the muscular layer. These glands open into the recesses of the mucosa.

1. Lingual Papillae

The body of the tongue (anterior 2/3), on its dorsal surface, is covered with the specialization of epithelium called the lingual papillae. The lingual papillae are projections of lamina propria covered with stratified squamous epithelium, which may be keratinized. Many papillae contain taste buds.

The papillae are of four types:

1. Filiform
2. Fungiform
3. Circumvallate and
4. Foliate.

The foliate papillae are not well-developed in humans

1. Filiform Papillae:

These are most numerous ofthe lingual papillae, covering most of the anterior 2/3 of the tongue. These are conical projections about 2-3 mm in length. Their tips are keratinized. These papillae are distributed in parallel rows. Filiform papillae contain no taste buds: the increase the friction between the tongue and food

2. Fungiform Papillae:

They are found distributed among the filiform papillae. Their shape is like a mushroom (narrow base with globular upper end) and they project above the filiform papillae. They have highly vascularized connective tissue cores: hence, visible on as red dots. The taste buds are present in the epithelium on its dorsal surface

3. Circumvallate Papillae:

• Circumvallate papillae are situated just in front of the sulcus terminalis.
• They are about 8- 16 and each one measures about 1- 2 mm in diameter.
• Each papilla is surrounded by a circular sulcus (trench). The stratified squamous epithelium, covering the free surface, is smooth while the epithelium covering the walls of the sulcus (trench) contains many taste buds.
• At the bottom of the trench, there are openings in the ducts of serous glands on Ebner, which are situated in the submucosa. The secretion of these serous glands keeps the sulcus rinsed.
• A core of connective tissue, supporting vessels, lymphatics and nerves fills the papillae

Papillae Remember:

Three common papillae found in humans are filiform fungiform, and circumvallate. Taste buds are present in fungi form and circumvallate papillae. The foliate papillae are not well-developed in humans

2. Taste Buds

Taste buds are neurosensory epithelial structures embedded in the surface epithelium of the tongue.

• The taste buds are also present in the epiglottis, soft palate and oropharynx. Tongue, they are present in the epithelium of fungiform and circumvallate papillae
• Taste buds appear as onion-like, oval, pale staining epithelial structures.
• 50-80 pm in length and 30-50 pm in width. The length of the taste bud extends through the full thickness of the epithelium vertically.
• The cells of taste buds are long and vertically oriented. Their tapering apical ends converge on a small depression (opening) on the surface of the epithelium. This depression (operating) js ca|iecj as taste pore

Three different types of cells are present in the taste blends:

1. Neuroepithelial cells or Receptor cells
2. Supporting cells and
3. Basal (stem) cells

These are

1. The neuroepithelial (receptor) cells:
   • The neuroepithelial and supporting cells are elongated and extend from the basal lamina to the taste pore.
   • Both kinds of cells send their microvilli in the taste pore.  Nerve axons form a plexus around each taste bud.
   • Their branches penetrate the basal lamina of the taste bud and make contact with the receptor cells. It is believed that this cell type is the principal taste receptor
2. Supporting cells:  The supporting cells besides providing support to receptor cells, also secrete an amorphous dense material at the taste pore.
3. Near the basal lamina:  Near the basal lamina there are small dark cells called basal or stem cells. The function of basal cells is to provide new receptors and supporting cells by their mitotic activity.

Taste is a chemical sensation. Various types of chemicals (tastants) stimulate neuroepithelial (receptor) cells of taste buds. We can feel sweet, salty, bitter, sour and delicious tastes through our receptor cells.

The tastants, which are with salt and sour taste act by opening and passing through ion channels of neuroepithelial cells. The sour tastants act by closing ion channels while bitter, sweet and delicious
tastes act by acting on specific taste receptors present in neuroepithelial cells.

Taste buds Remember:

Taste buds appear as onion-like, oval, pale staining epithelial structures. Three different types of cells are present in the taste buds: receptor cells, supporting cells and basal (stem) cells. We can feel sweet, salty, bitter, sour and delicious tastes through our receptor cells

3. Muscles of the Tongue

The core of the tongue (beneath the mucous membrane) contains striated muscle. The muscle fibres are arranged in transverse, longitudinal and vertical bundles. In between the muscle bundles, variable amounts of loose connective tissue, adipose tissue and lingual glands are found.

Salivary Glands

The salivary glands are accessory glands of digestion and pour their secretion (saliva) into the oral cavity.

There are two kinds of salivary glands:

1. Minor salivary glands: These are small salivary glands situated in the mucous membrane ofthe lip (labial), cheeks (buccal), soft palate (palatine) and tongue (lingual).
2. Major salivary glands: These are parotid, submandibular and sublingual glands. Each of these glands lies completely outside the alimentary tract and is connected to it by an excretory duct. These glands are classified as compound alveolar or tubuloalveolar.

Salivary Glands Functions

Salivary glands secrete saliva, which is composed of water, mucus, proteins, salts, salivary amylase (ptyalin immunoglobulins (particularly IgA), and lactoperoxidase

• It serves to moisten food
• Lubricates and moistens oral mucosa and lip.
• It initiates the digestion of carbohydrates.

Basic Organization of Salivary Glands

As stated earlier, the major salivary glands are compound glands that consist of multiple acini at the end of the highly branched duct system.

• An acinus is defined as a group of secretory cells that are arranged around a narrow lumen.
• The duct and acini of the salivary gland resemble a bunch of grapes in which ducts represent the branching stem and acini represent the grapes.
• Acini are made up of either serous or mucous cells.
• There may be a mix of both serous and mucous acini these are called mixed salivary glands.
• In addition, some of the mucous acini may have a cap of serous cells called the parotid gland is chiefly a serous, while submandibular and sublingual are mixed glands.
• A salivary gland contains branching ducts, which are classified as in intralobular (intercalated and striated), interlobular, lobar and main excretory ducts.
• These ducts are lined by cuboidal (intercalated), columnar (striated), pseudostratified columnar (interlobular), stratified cuboidal (lobar) and major excretory ducts are lined by stratified columnar epithelium.

Salivary glands Remember:

Major salivary glands consist of multiple acini at the end of the highly branched duct system. Acini are of three types: serous, mucous or mixed. Some of the mucous acini may have a cap of serous cells called serous demilune. Ducts are classified as intralobular (intercalated and striated), interlobular, lobar and main excretory ducts

Salivary glands other Details Of Basic Organization:

A salivary gland consists of two components

1. Connective tissue component
2. Parenchymal components (ducts and acini)

The parotid and submandibular glands are surrounded by a well-developed connective tissue capsule. Septa arising from the capsule enter the parenchyma of the gland and divide the gland into lobes and lobules.

The acini and intralobular ducts are enveloped by delicate connective tissues. The connective tissue septa form a medium through the parenchymal component of the salivary gland consisting of acini and ducts.

The acini are composed of pyramidal secretory cells, which are arranged around a narrow lumen and surrounded by myoepithelial cells. The myoepithelial cells are present between secretory cells and basal lamina The lumen of acini is continuous with the duct system

Duct System

The main excretory duct of a salivary gland divides to give lobar and interlobular ducts. The interlobular ducts further divide to give intralobular ducts. The intralobular ducts are of two types, i.e., intercalated and striated. The lumen of the intercalated duct opens directly into the acinus.

1. Intercalated Ducts:

The intercalated ducts arc of short length and serve to connect acini with the striated ducts.

• These ducts are lined by short cuboidal ceils or sometimes by simple squamous epithelium.
• The cells of intercalated ducts, similar to acini may also be surrounded by myoepithelial cells.
• Intercalated ducts are prominent in the serous glands. They secrete HCO₃^– into the acinar product and absorb Cl^– from the product.

2. Striated Ducts:

The striated ducts connect interlobular ducts to intercalated ducts. These ducts are lined by simple columnar epithelium.

• These cells are stained bright pink in H&E preparation and have nuclei located near the lumen.
• These cells also show basal striations, which are due to the vertical orientation of mitochondria lodged between basal infoldings of the plasma membrane.
• This characteristic is typical of cells engaged in salt and water transport.

The intercalated and striated ducts are predominantly present in serous glands. These ducts are involved in the modification of the serous secretion (by absorbing certain constituents and secreting others, i.e., secretion of K⁺ and HCO₃^– and absorption of Na⁺).

As the mucus secretion is not modified while passing through the duct, the intercalated ducts are poorly developed and striated ducts are absent in mucous glands.

Striated duct Remember:

The basal plasma membrane of striated duct cells is highly folded. The longitudinally oriented, elongated mitochondria are enclosed in these foldings. Striated ducts are the sites of reabsorption of sodium and secretion of potassium

3. Interlobular, Lobar and Main Excretory Ducts:

These larger ducts are lined by epithelium that ranges from simple columnar to pseudostratified columnar (interlobular ducts) to stratified columnar or stratified cuboidal (lobar and main excretory ducts) At its opening in the oral cavity, it may be lined by stratified squamous epithelium. These ducts are surrounded by a large amount of connective tissue.

The Secretory Acinar System

The acini are described as

1. Serous
2. Mucous and
3. Mixed

1. Serous Acini:

Serous acini have a small lumen and produce a clear watery secretion. Serous cells are usually pyramidal and have rounded nuclei located near the base.

• A large amount of rough endoplasmic reticulum and free ribosomes are present near the base.
• Because of this acini are stained with haematoxylin (basophilic) near the base.
• Above the nucleus and Golgi complex, apical secretory granules (zymogen granules) are present.
• The presence of secretory granules is responsible for the staining of the apical portion by eosin.

2. Mucous Acini:

The mucous acini arc is usually tubuloalveolar and has relatively wide lumens.

• Mucous cells arc roughly pyramidal or columnar and have flattened nuclei situated near their base.
• The apical portion of the cell contains mucus, which is stored in the form of mucinogen granules.
• Because the mucus is lost in the preparation of H&E-stained paraffin sections,
• The apical portion ofthe cell is not stained and shows an empty appearance

3. Mixed Acini:

Submandibular and sublingual salivary glands contain both (serous and mucous) types of acini. In addition, some ofthe mucous acini may have the cap of serous cells called serous demilune.

Differences between serous and mucous acini:

Myoepithelial Cells (Basket Cells):

These star-shaped (branched) cells are present between the epithelium and basal lamina of the acinus and the proximal part of the duct. They contain actin filaments and hence are contractile. Their contraction is thought to help in expelling the secretion from the lumen facing.

Parotid Gland

The parotid gland is the largest salivary gland. It has a well-defined capsule. Septa divide the gland into lobes and lobules.

1. Secretory acini: The acini are purely serous The gland has abundant myoepithelial (basket) cells that help to expel the secretory product from the lumen of the acinus
2. Ducts: The interlobular ducts are present in the connective tissue septa. These ducts may be lined by simple columnar or pseudostratified columnar epithelium. The intralobular ducts are seen between acini. The intercalated ducts are lined by simple squamous to low cuboidal epithelium.

They are long and branching in the parotid gland. The striated ducts are lined by simple low columnar epithelium and show basal striations. The striations are responsible for the bright eosinophilic (acidophilic) staining reaction of these ducts The adipose tissue may be seen among acini and smaller ducts.

Parotid gland Clinical Applications

Mumps:

The infection of the parotid gland by mumps virus (Myxovirus) is called mumps. In this disease, there is swelling and enlargement of the parotid gland and severe pain in the throat. The infection may also spread to other salivary glands. The disease is self-limiting

Submandibular Gland

The submandibular gland is a mixed gland. It has a well-defined capsule and septa, which divide the gland into lobules.

• Secretory acini: It consists of both serous and mucous acini However, sometimes the serous acini are more than mucous. At certain places, mucous acini are capped by a layer of serous cells, which may present a half-moon appearance in some sections; hence, they are called serous demilunes.
• Ducts: The epithelial lining of the main, interlobular and intralobular ducts are the same as in the parotid gland. However, the striated ducts of the submandibular gland are large and branching; hence, many are seen between acini.

Serous demilunes are, not the true histological structures:

The serous demilunes are observed in the mixed salivary gland (both under light and electron microscopes) after the tissue is fixed by the routine fixation method. However, when

• The tissue is preserved by the rapid freezing method and observed under the transmission electron microscope, a different kind of histological structure of the gland is observed.
• Here, the acini of mixed glands consists of both serous and mucus-secreting cells.
• One end of these cells rests on the basal lamina and the other end projects into the lumen of acini. Both the serous and mucous cells arc almost of the same size.
• The serous cells arc pyramidal in shape and the shape of mucous varies from short columnar to pyramidal.
• The mucous cells contain centrally located rounded nuclei and many mucinogen granules in the apical region.
• Both types of cells pour their secretion into the lumen of acinus. This appearance ofthe mucous cells seems to be the real one as the rapid freezing method preserves the tissue with minimal alteration in its morphological structure and chemical composition.

The acini, as seen in resembles the above description of tissue preserved with the rapid freezing method.

• However, when the tissue slides are prepared by using routine chemical fixative (usually formaldehyde), then the fixative causes the swelling of mucinogen granules in the mucous-secreting cells.
• This pushes the nucleus ofthe cell towards the basal lamina, which under the pressure of mucinogen granules becomes flattened. These swollen mucous cells also push the pyramidal-shaped serous cells towards the periphery of the acinus.
• It appears as if mucous acinus has having crescentic-shaped cap of serous cells, which is traditionally described as serous demilune

The tissue was obtained from an adult goat and preserved in formaldehyde.

Even though this tissue was not preserved by the rapid freezing method, its ducts showed similar features as described for rapid freezing fixed tissue.

 

Question 1. Why we must have found these kinds of mixed acini after routine fixation?
Answer:

The possible explanation for this may be that the goat is a ruminating animal as partially digested cud comes back in its mouth at intervals. As these animals constantly chew, the saliva is also produced constantly in large quantities.

This may be the reason for the nonaccumulation of a large quantity of mitogen granules in the mucous-secreting cells in a goat. During chemical recreation, though these granules swell they may not exert much pressure on the neighbouring serous cells. Thus, in most ofthe mixed acini serious demilunes fail to form

The above description indicates that not only the serous demi lunes but also the large size of mucous cells, the basal position and the flattered shape of its nuclei are also the artefacts of chemical fixation.

Chemical fixation Remember:

Serous demilunes and mucous cells as observed in histological slides after chemical fixation, are not the true histological structure but are artefacts of chemical fixation.

Differences between serous and mucous cells

Sublingual Gland

It has no definite capsule. The septa divide the gland into lobules

• Secretory acini: The sublingual gland is made up predominantly of mucous-secreting acini  Some mixed acini with serous demilunes are also io seen. The pure serous acini are rarely seen. Thus, it is classified as a mixed salivary gland.
• Ducts: The main and interlobular ducts are present. Very’ few striated ducts are seen in this section. Intercalated ducts are difficult to find (rarely seen).

Connective Tissue Proper

Classification Of Connective Tissue

1. Embryonic connective tissue
   • Mesenchyme
   • Mucous connective tissue(areolar tissue)
2. Connective tissue proper
   • Loose connective tissue(areolar tissue)
   • Adipose tissue
   • Reticular tissue
   • Dense connective tissue
     1. Irregular dense connective tissue
     2. Regular dense connective tissue
     3. Elastic connective tissue
3. Specialized connective tissue
   • Cartilage tissue
   • Bone tissue
   • BIood

In the previous chapter, we studied the basic components of general connective tissue, i.e., ground substance, fibers, and cells. All three components are present in all types of connective tissues.

• However, the proportions of various fibrous and amorphous components vary from one connective tissue type to the other.
• For example, dense connective tissue consists predominantly of fibers, but a very small amount of ground substance and few cells.
• On the other hand, loose connective tissue consists predominantly of ground substances and cells but very few fibers. Following is a brief description of various connective tissues.

Embryonic Connective Tissue

Embryonic connective tissue is classified into two subtypes, i.e., mesenchyme and mucous connective tissue.

Mesenchyme

It consists of small spindle-shaped cells with many processes. Processes of neighboring cells are in contact with each other through a gap junction.

Space between cells is occupied by ground substance and reticular fibers. Mesenchy mal cells are found in the embryo.

Mucous Connective Tissue

It consists of spindle-shaped cells with long and thin cytoplasmic processes. Large intercellular spaces are occupied by jelly-like matrix and thin collagen fibers.

The ground substance of the umbilical cord is also called Wharton’s jelly.

Loose Connective Tissue

Loose Connective Tissue Description

Loose or areolar connective tissue is the most widespread
of all the connective tissues. It consists of a loosely woven network of fibers (all types of fibers are present-collagen, elastic, and reticular).

• Almost all kinds of connective tissue cells(fibroblasts, macrophages, plasma cells, fat cells, white blood cells, and mast cells) are present.
• Fibers and cells are embedded in a semi-fluid ground substance that consists of hyaluronic acid and chondroitin sulfate.

Loose Connective Tissue Location

• It lies beneath the epithelium as lamina propria.
• It is present in superficial fascia along with the adipose tissue.
• It surrounds blood vessels, nerves, viscera muscle, etc.
• It is also present in the mesentery.
• It surrounds the parenchyma of glands.
• It lies below the mesothelium of body cavities.

Loose Connective Tissue Functions

It provides support to the epithelium. It acts as packing material around various structures and thus provides strength, support, and elasticity.

• There occurs the secretion of histamine by mast cells in inflammatory conditions. Histamine causes increased permeability of blood capillaries.
• This leads to a collection of excessive fluid in loose connective tissue resulting in swelling or edema.

Loose Connective Tissue Remember

Loose connective tissue consists of a loosely arranged network of fibers and almost all kinds of connective tissue cells embedded in a gel-like ground substance.

1. Low magnification photomicrograph of oesophagous.
2. Magnified view of loose connective tissue.

Adipose Tissue

Adipose tissue or fat can be classified into two types, i.c., white adipose tissue(unilocular fat) and brown adipose tissue (multilocular fat).

White Adipose Tissue Description

The color of adipose tissue(fat) is white or yellowish. This tissue is formed by the aggregation of adipocytes(fat cells). Fat cells arc polyhedral or oval.

• Their size is quite large(up to 100 pm), Within a fat cell there is the presence of a single large droplet of lipid (unilocular) that pushes the nucleus to one side and the cytoplasm is present in the form of a thin rim around it.
• Adipocytes are surrounded by the reticular fibers; while groups of adipocytes arc surrounded by connective tissue septa. Adipose tissue is rich in blood vessels. Adipose tissue stores the nutritional calories.

White Adipose Tissue Location

Adipose tissue is present in superficial fascia deep to the skin, bone marrow, omentum, mesentery, and around some viscera(heart, kidney, eyeball, etc).

White Adipose Tissue Functions

It serves as an energy reserve that supports and protects the structures, which surround and prevent heat loss through the skin.

1. Adipose cells are placed close to each other. These cells are separated by a small amount of connective tissue in which blood vessels run
2. An adipose(fat cell) appears as an empty cell with a flattened nucleus compressed in the peripheral rim of the cytoplasm
3. Multilocular adipose cells of brown adipose tissue
4. In this photomicrograph of adipose tissue(H and E) lipid contents of fat cells are extracted during tissue processing.

Brown Adipose Tissue

The brown adipose tissue of fat is found only at certain places in the newborn human body, i.e., the posterior triangle abdominal wall. Here, it prevents the excessive heat loss from the body surfacing.

The cells of brown fat differ from the white or yellowish fat in two ways, i.e., the nucleus is not flat but may be pushed to one side, and fat contained in the cytoplasm is in the form of small drops (Multilocular).

Brown Adipose Tissue Remember

Brown fat is not present in mature humans. It is present only in newborns and children and is gradually replaced by white fat (thus changing from multilocular droplets to unilocular droplets of fat within adipose cells).

Brown Adipose Tissue Functions

The function of the brown adipose tissue is to maintain normal body temperature in newborns. This is regulated by the thermogenin protein present in the mitochondria.

Reticular Connective Tissue

Reticular Connective Tissue Description

The reticular tissue consists of a mesh-like network of reticular fibers and reticular cells. Reticular fibers are type 3 collagen.

These cells tend to be star-shaped with radiating processes. Some consider that these cells are not distinct types but fibroblasts. Reticular tissue also consists of macrophages.

Reticular Connective Tissue Location

This tissue forms the architectural framework in the spleen, lymph nodes, liver, glands, bone marrow, reticular lamina of the basement membrane, and around smooth muscle cells.

Reticular Connective Tissue Functions

• It provides structural support to various organs by forming stroma or reticular framework.
• Reticular cells may be phagocytic.
• It binds smooth muscle cells.

Reticular Connective Tissue Remember

It is believed by some that reticular cells are not different from fibroblasts.

Dense Connective Tissue

Dense connective tissue contains a large amount of fibers and few cells as compared to loose connective tissue. This connective tissue may be subdivided into three types, i.e., dense irregular, dense regular, and elastic connective tissues.

Dense Irregular Connective Tissue Description

This tissue consists predominantly of collagen fibers. In this tissue, the bundles of collagen fibers are randomly(irregularly) oriented.

Fiber bundles are coarse and form a compact network with little spaces occupied by few connective tissue cells and little ground substance. Fibroblasts are present between bundles.

Dense Irregular Connective Tissue Location

It is present in the dermis of the skin, dura mater, epimysium, epineurium, pericardium, periosteum, tunica albuginea of testis, sclera, capsule of various organs, and submucosa of the intestinal tract.

Dense Irregular Connective Tissue Functions

It provides strength to the tissue.

Dense Regular Connective Tissue Description

This tissue also consists predominantly of collagen fibers (type 1). Bundles of collagen fibers are arranged regularly and parallel to the direction of stress, i.e., as in the case of tendons and aponeuroses.

Fibroblasts are present in rows between bundles of collagen fibers. Bundles of collagen fibers are so closely packed that very little space is left for ground substance and loose connective tissue through which run small blood vessels.

Dense Regular Connective Tissue Location

This tissue is present in tendons and aponeuroses of muscles and ligaments.

Dense Regular Connective Tissue Functions

Tendons, aponeuroses, and ligaments provide great resistance to pulling force but at the same time are flexible.

1. Longitudinal section of tendon showing bundles of collagen fibers arranged parallel to each other.
2. Transverse section of a tendon. Between the collagen bundles note the presence of loose connective tissue and blood vessels.

Elastic Tissue Description

Few elastic fibers are found in almost all types of connective tissues. However, in certain situations, elastic fibers are predominantly present.

• In these situations, connective tissue is called clastic connective tissue. This type of connective tissue consists of layers of freely branching elastic fibers.
• Fibroblasts and ground substances are present in small spaces intervening between fibers.

Elastic Tissue Location

Elastic tissue is found in the fascia of the anterior abdominal wall; a wall of the aorta and large arteries; trachea and bronchi; vocal cords; ligamentum nuchae; ligamentum flavum and in the suspensory ligament of the penis.

Elastic Tissue Functions

K provides elasticity to tissue.

Elastic Tissue Clinical Applications

• Obesity
  • Obesity in adults may result due to the accumulation of excessive fat in white adipose cells so that cells become larger than usual. Sometimes, an increase in the number of adipose cells may also occur.
• Lipoma
  • The most common adipose tissue tumor is called lipoma. They are usually found in the subcutaneous tissue of middle-aged persons. These are benign tumors (not cancerous).
• Liposarcoma
  • It is a malignant tumor of adipose tissue, which is quite rare.

Respiratory System

The respiratory system consists of the nose, pharynx larynx, trachea and lungs.

Respiratory System is concerned with the following functions:

• Perception of smell: The olfactory mucosa of the nasal cavity contains receptors for the sense of smell
• Filtration of inhaled air: The upper respiratory mucosa of the nasal cavity contains receptors for the sense of smell.
• Phonation: The Larynx helps in the production of sounds. The larynx also prevents the entry of solid food, liquid and foreign bodies into the trachea and lungs
• Respiration: Exchange of gases, i.e., intake of O and elimination of ofCOr This process of exchange of gases is called respiration.
• Maintenance of blood pH: It participates in the regulation of blood pH.

Functionally, the respiratory system consists of two factors:

1. Conducting part: It conducts the air from nose to lung and consists of the nasal cavity, pharynx, larynx, trachea, bronchi, bronchioles and terminal bronchioles. The trachea bronchi and bronchioles are branching systems of tubes The conducting part also filters, warms and moistens the while passing through it
2. Respiratory part: It is located strictly within the lungs and consists of spongy respiratory tissue of the lungs across which blood and air exchange their gases.It consists of respiratory bronchioles, alveolar ducts, alveolar sacs and alveoli

The Conducting Part Of The Respiratory System

The conducting part of the respiratory system consists of the

1. Nasal cavity,
2. Nasopharynx
3. Larynx
4. Trachea and Primary bronchi
5. Intrapulmonary bronchi and
6. Bronchioles.

Histology of Nasal Cavity, Nasopharynx and Larynx:

1. Nasal Cavities

The nasal cavities repaired chambers separated by septum. Each nasal cavity is a hollow organ composed of bone, cartilage and connective tissue covered by mucous membrane. The nasal cavity chamber is divided into three regions, i.e., nasal vestibule, respiratory region and olfactory region.

Nasal vestibule:

This is the most anterior dilated part. the nasal cavity. It is situated inside the nostril and lined by hair skin These hair filter large particles from in Spired air

Respirators- region:

It is the largest part of the nasal cavity. It is occupied by the lower 2/3 part of the nasal cavity. The respiratory portion of the nasal cavity is lined with pseudostratified ciliated columnar epithelium with goblet cells.

• Underlying this epithelium, aminapropria contains ser°us mucus-secreting glands, large venous plexus, lymphatic tissue collection, plasma cells and macrophages
• Cilla on tall colour cells act as filter and their beatings carry foreign matter and mucus towards the oropharynx where they are swallowed’ The goblet cells Produce mucus to trap foreign particles and keep the membrane moist
• The cells in lamina propria (lymphocytes, plasma cells macrophages, etc) serve aprotective function.
• The large venous plexus warms the air, and seromucous glands provide the moisture and mucus.
• Thus, while passing through the nasal cavity, the air is conditioned, i.e., it is wanned, moistened and freed of dust particles.
• The upper respiratory tract is exposed to a wide variety of pathogens in the process of warming, humidifying and filtering the inspired air.
• These organisms may lodge and grow in the host This may lead to an upper respiratory infection (sore throat tonsillitis and infection of paranasal air sinuses)

Respiratory system Remember:

The inhaled air is conditioned before reaching the lung alveoli. This is achieved by warming, humidifying and filtering the inspired air while it is passing through the conducting part of the respiratory system.

 Olfactory region:

It is occupied by the upper 1/3 part of the nasal cavity near its apex. It is lined by specialized olfactory mucosa. The total area of olfactory mucosa is only about 1 0 cm² area. The epithelium of olfactory mucosa is pseudostratified.

Composed of the following types of cells:

1. Olfactory receptor cells: These are modified bipolar neurons that send axons to the olfactory nerve. Their apical portion bears cilia (hair).
   • These cilia are involved in olfactory transduction pathways.
   • Cilia have numerous odour receptor molecules.
   • The molecules of odoriferous substance dissolved in serous fluid bind to the specific receptor molecules.
   • This generates the action potential and information is passed to the brain
2. Supporting cells: These are long columnar cells which provide mechanical support to olfactory receptor cells
3. Basal cells: These are present near the basement membrane. They differentiate into receptor and supporting cells
4. Olfactory glands (Bowman’s glands): These are present in the lamina propria. They deliver their proteinaceous secretion via ducts onto the olfactory surface

Olfactory Remember:

The olfactory mucosa is pseudostratified and composed of olfactory receptor cells, supporting cells and basal cells. Olfactory glands (Bowman’s glands) are present in the lamina propria.

2. Nasopharynx

It lies between the nasal cavity and the oropharynx. The nasopharynx is also covered with pseudostratified ciliated columnar epithelium goblet cells.

3. Larynx

It begins with the epiglottis and ends at the trachea. Most ofthe parts ofthe larynx are also covered by pseudostratified ciliated columnar epithelium with goblet cells. Lamina propria at places may contain seromucous glands and lymphatic tissue.

Epiglottis:

The epiglottis consists of a plate of elastic cartilage in the middle. On both the sides of cartilage, there is the presence of lamina propria. Lamina propria contains seromucous glands. The anterior surface (facing tongue) and upper part of the posterior surface of the epiglottis are lined by stratified squamous epithelium.

The remaining pan of the posterior surface is lined by pseudostratified ciliated columnar epithelium with goblet cells.

4. Trachea and Primary Bronchi

The histological structures of the trachea and primary bronchi are essentially the same. The trachea is a flexible tube measuring about 11 cm in length and 2 cm in diameter. Its wall contains 1 6-20 C-shaped hyaline cartilages, which keep the lumen of the tube patent. The gap between the free ends of a C is bridged by a muscle called the tracheal

The trachea divides into two principal (or primary) bronchi The trachea and primary bronchi consist of four layers.

• Mucous membrane (epithelium and lamina propria): The epithelium is a pseudostratified ciliated columnar with goblet cells. The epithelium rests on thick basal lamina. Three different types of common cells of epithelium are ciliated cells (30%), goblet cells (28%) and basal cells (29%).
  • The ciliated cells propel the mucus upwards and their percentage increases from the upper to the lower trachea.
  • The goblet cells produce mucus. The basal cells are small pyramidal cells situated near the basal lamina.
  • They act as stem cells that can divide and differentiate to replace other cell types
  • The other two less common cells are granule cells Kulchitsky cells) and brush cells.
  • The small granule cells are situated at the base ofthe epithelium and contain dense secretory granules in an intranuclear position.
  • These cells discharge their contents in response to hypoxia. The brush cells contain large microvilli with an actin filament core extending down into the cytoplasm.
  • The nerve terminals are seen in these cells. These cells contain no secretory granules and may have sensory functions
  • The lamina propria of the trachea and principal bronchi is made up of loose connective tissue, which is rich in elastic fibres.
  • It may also contain lymphatic tissue, in both diffuse and nodular forms.
•  Submucosa: In the trachea, it is difficult to distinguish the boundary between lamina propria and submucosa.
  • At the junction of the two, there is a dense layer of elastic fibres, which is seen with a special stain.
  • The submucosa contains mixed seromucous glands whose ducts open onto the surface epithelium
• Cartilage and smooth muscle layer: This layer consists of a hyaline cartilaginous ring separated by interspaces bridged by fibroblastic connective tissue.
  • The rings of cartilage are incomplete posteriorly.
  • The gap is filled by smooth muscle (tracheal) and by fibroblastic tissue.
• Adventitia: External to the cartilaginous ring, there is a layer of connective tissue that is rich in elastic fibres.

Trachea and primary branch Remember:

The trachea and primary bronchi consist of four layers, i.e., mucosa (lined by pseudo-stratified ciliated columnar epithelium with goblet cells resting on lamina propria) submucosa (contains mixed seromucous glands, cartilage and srn°°th muscle layer and adventitia.

5. Intrapulmonary Bronchi

The primary bronchi enter the lung through the hilum. In the lung, primary bronchi branch into lobar bronchi, which in turn divide into segmental bronchi. The segmental bronchi branch many times as they penetrate further into the lung, resulting in many orders of decreasing diameter.

Following are the layers observed in the intrapulmonary bronchi:

• Mucosa: The epithelium is pscudoslrati tied ciliated columnar with goblet cells. The lamina propria contains many clastic fibres and seromucous glands
• Smooth muscle layer: The smooth muscle layer is present in lamina propria beneath the epithelium Smooth muscle is arranged in bundles, which run spirally. Elastic fibres arc intermixed with muscle
• Submucosa: It consists of the loose connective tissue in which glands are embedded.
• Cartilage layer: In contrast to C-shaped cartilage present in the trachea, the intrapulmonary bronchi contain irregular plates of cartilage. These cartilaginous plates surround the bronchi and keep them open. Therefore, intra-pulmonary bronchi are always cylindrical rather than flattened on one side as arc the trachea and primary bronchi.
• Adventitia: Outside the cartilage layer adventitia is made up of the connective tissue layer

As the bronchi divide repeatedly and become smaller in size each component of the wall becomes thinner and sparser, except the layer of smooth muscle, which remains distinct The submucosal glands gradually decrease in number and end at the level ofthe bronchiole.

Intrapulmonary Bronchi Remember:

In contrast to the trachea, bronchi contain circumferentially arranged smooth muscle layers in lamina propria and irregular plates of cartilage

6. Bronchioles

Bronchioles are defined as conducting tubules that are less than 1 mm in diameter and their wall no longer contain The bronchioles further divide to end in the terminal bronchioles, which are the terminal segments ofthe conducting portion of the respiratory tract. Terminal bronchioles subdivide into microscopic branches called respiratory bronchioles.

Following are the layers observed in bronchioles:

• Mucosa: The type of epithelium varies with the size of the bronchiole. Large bronchioles have simple ciliated columnar cells with very few goblet cells.
  • The smaller bronchioles have simple cuboidal ciliated cells with no goblet cells. The Clara cells replace the goblet cells.
  • These cells are non-ciliated but have many microvilli on their apical surface.
  • They first appear in small bronchi but greatly increase in number of terminal bronchioles.
  • Clara cells are considered to secrete a lipoprotein, which forms a protective layer of surface active agents throughout the lower respiratory tract.
  • Surface active agent reduces the surface tension of the alveolar fluid, which reduces the tendency of alveoli to collapse. It also prevents the adhesion between walls forming a lumen of air passage, especially during expiration.
  • Clara cells also produce a 16-kilodalton protein known as Clara cell secretory protein (CC16). Seromucous glands are not present in the lamina propria of bronchioles.
• Smooth muscle layer: It is a prominent layer and a major component of the wall. The smooth muscles are supplied with sympathetic and parasympathetic nerves.
  • Normally, the muscle layer regulates the passage of air through it.
  • But sometimes the hyperirritability of the respiratory tract may lead to the excessive contraction of smooth muscle
  • This results in the constriction of bronchi and bronchioles and may cause difficulty in breathing. This condition may arise in a person suffering from asthma
• The connective tissue layer:
  • Outside the muscle coat, the bronchioles are surrounded by lung alveoli.
  • The bronchioles and lung alveoli are connected with the connective tissue layer, which is rich in elastic network

Bronchioles Remember:

Bronchioles are less than 1 mm in diameter. Cartilage plates and glands are absent. However, Clara cells are present in their epithelial lining.

Differences between bronchus and bronchiole:

Conducting part of respiratory system Clinical Applications

Asthma

Asthma is an acute, episodic, airway obstruction that results from an allergy to a variety of substances (such as pollen, house dust, mites, moulds or a particular food).

• A person suffering from asthma tends to develop bronchospasm, which leads to obstruction of airways and air trapping.
• The bronchospasm (airway obstruction) may be due to smooth muscle spasm in the wall of smaller bronchi and bronchioles, increased secretion of mucus and swelling of mucosa
• A person suffering from asthma has difficulty in breathing, tightness in the chest, cough and anxiety.
• Asthma is treated with drugs, which relaxes smooth muscles in the bronchioles and opens up the airways.

The Respiratory Part Of Respiratory System

Respiratory Bronchioles, Alveolar Ducts and Alveolar Sacs and Alveoli

1. Respiratory Bronchioles

• Respiratory bronchioles are the site of transition from the conducting part to the respiratory part.
• It is called respiratory bronchiole because it is partly respiratory in function
• A respiratory bronchiole usually measures less than 0.5 mm in diameter
• The respiratory alveoli are present in its wall as outpouching.
• The epithelium is simple cuboidal with cilia, which are gradu¬ ally lost and are replaced by non-ciliated low cuboidal cells
• The Clara cells are also present in between cuboidal cells
• A smooth muscle layer is still present outside the epithelium
• Outermost covering is ofdelicate connective tissue.

2. AlveolarDucts and Alveolar Sacs

Each respiratory bronchiole ends by dividing into 2 or 3 alveolar ducts. Many alveoli and alveolar sacs open into the alveolar duct. At the end of the alveolar duct, the clusters of alveoli share a common opening to the alveolar duct. This cluster of alveoli is called as alveolar sac.

3. Alveoli

These are thin-walled polyhedral sacs, one side of which is always lacking. Alveoli are round or polygonal in shape and about 200 pm in diameter.

• They consist of pure respiratory surfaces across which gaseous exchange occurs.
• Alveoli are closely packed, so the alveolar wall is a partition 2 present in their epithelial lining.
• Remember or septum between two alveoli. The interalveolar septa contain a network of capillaries, supported by reticular and elastic fibres, and occasionally fibroblasts and macrophages between the squamous epithelium of adjacent alveoli.

There may be openings in septa, which are called pores. These pores help in the circulation of air from one alveolus to another, thus equalizing the pressure in the alveoli. The alveolar pores play another important role in case of blockage of air passage.

The alveoli distal to the blockage may get air from the alveoli of neighbouring lobules. Wherever the endothelium of the capillary comes in contact with the alveolar epithelium no connective tissue lies in between the two.

Respiratory bronchioles Remember:

Respiratory bronchioles are partly respiratory in function where the exchange of gases occurs. Alveolar duct, atria and alveoli are supplied by rich capillary network and are the site of gas exchange

The blood-air barrier:

The air in the alveolus is separated from the blood in the capillary by following three structures

• Continuous non-fenestrated endothelium of capillary.
• Squamous epithelium lining the alveolus.
• The fused basal lamina of endothelium and epithelium

This thin (1.5 – 2μm) blood-air barrier facilitates the diffusion of oxygen and carbon dioxide.

4. Cells of Alveolar Wall (septum)

The alveolar wall (septum) is covered with the following types of epithelial cells

Type 1 alveolar cells (squamous epithelial cells/pneumocyte 1):

These are very thin squamous cells. These cells cover over 95% ofthe alveolar surface

Type 2 alveolar cells (great alveolar cells/ pneumocyte):

These are large rounded cells, which bear microvilli on their apical surface. These cells are placed in between type 1 cells and the remaining 5% surface area of alveoli.

• Type 2 alveolar cells are secretory and secrete the pulmonary surfactant, which lowers surface tension and prevents alveoli from collapsing during expiration.
• When viewed under electron microscope an electron microscope the secretory granules of these cells show a peculiar appearance.
• These granules contain membrane-like layers arranged parallel one upon the other.
• These layers are made up mainly of phospholipids and proteins (precursors of surfactants). The surfactant is secreted continuously by cytosis.
• This kind of secretory granules is called s. Type 2 alveolar cells also give origin to type 1 alveolar cells. After lung injury, they give origin to type 1 and type 2 cells within lung alveoli.
• Besides secreting lipoprotein surfactant, type 2 cells also produce various types of proteins (surfactantprotein A, B, C and D). These proteins modulate alveolar immune responses.

Type 3 alveolar cells (brush cells):

• These cells are found only occasionally in the alveolar epithelium. These cells serve as receptors to monitor the quality of air entering the lung
• All cells forming the alveolar epithelium are joined to each other by zonula occludens.

Alveolar Remember:

95% of the alveolar wall is covered by type 1 pneumocytes, which are involved in the exchange of gases. The remaining 5% of the alveolar wall is covered by type 2 pneumocytes involved in the secretion of surfactant. Brush cells are also found occasionally in the alveolar epithelium. Brush cells serve as receptors to monitor the quality of air entering the lungs.

5. Alveolar Macrophage

These cells are found in the connective tissue of interalveolar septa. Some of these cells enter the connective tissue from blood and pass through the alveolar epithelium to reach into the lumen alveoli. Alveolar macrophages are the first line of defence against pulmonary infection.

They act in the following way:

• They phagocytose dust particles, which may be seen in their cytoplasm.
• Hence, sometimes they are also called dust cells.
• In cigarette smokers, they engulf carbon and tar
• They are also capable of phagocytosing bacteria In patients of heart failure (here pulmonary capillaries are overloaded with blood), erythrocytes may accumulate in alveoli.
• These erythrocytes are phagocytosed by macrophages, which acquire a brick-red colour because of the presence of haemosiderin (a product of haemoglobin degradation and are then called as heart failure cells.

The respiratory part of the respiratory system Clinical Application

Pneumonia

• It is an acute infection of the lung alveoli. Pneumococcal pneumonia is the most common bacterial pneumonia and represents a threat to the aged and chronically.
• When microorganisms enter the lungs, they produce toxins which in turn stimulate inflammation and immune response.
• This leads to a collection of exudates, plasma proteins, RBCs, fibrin and leucocytes in the alveoli.
• This interferes with ventilation and gas exchange.
• The clinical signs include fever, cough, chest pain, blood-streaked sputum and difficulty in breathing. Pneumonia is treated with antibiotics

Cigarette Smoking and Cancer of Lung

The association between cigarette smoking and cancer of the lung is well known.

• Although the bronchial tree is mainly lined by pseudostratified ciliated columnar epithelium, it changes to stratified squamous epithelium in chronic smokers because of the presence of toxic elements in smoke. (The epithelial alteration from one kind to another is known as metaplasia.)
• This transformation is the first step in the development of squamous cell carcinoma, which is the main type of cancer of the lung.

Different Types of Ceils ofRespiratory System and their functions

1. In the epithelium of the trachea, bronchus and bronchiole:

• Ciliated cells: Beating oftheircilia moves the mucus upward
• Goblet cells: These cells produce mucus, which traps the dust particles
• Basal cells: They multiply and give rise to another type of cell
• Granule cells: They are believed to be endocrine cells.
• Brush cells: Sensory
• Clara cells: Produce secretion, which reduces the surface tension in alveoli

2. In the epithelial lining of lung alveoli:

• Type 1 alveolar cells (pneumocytes 1/squamous cells): Exchange of gases occurs through these cells
• Type 2 alveolar cells (pneumocytes 2): These cells produce pulmonary surfactant, which prevents collapse ofthe alveolus during expiration.
• Brush cells: They are considered to be sensory cells.

3. About the lumen of lung alveoli:

Macrophages: They phagocytose dust particles (dust cells) or erythrocytes (heart failure cells).

Distribution of epithelium in various parts of respiratory passage:

Introduction to Connective Tissue Components

What is Connective Tissue?

Connective Tissue Definition:

Connective tissue is a term that is used for a widely dispersed group of tissues performing a variety of functions. As the name suggests, connective tissues serve as a connecting system binding, supporting, and strengthening all other tissues together.

• It protects and insulates internal organs by forming capsules, sheaths, or septas. Blood, a fluid connective tissue, acts as a major transport system within the body.
• Fat is stored in the superficial fascia, which is a major site for the storage of energy reserves and provides insulation against heat loss from the skin. Blood vessels and nerves enter or leave an organ by passing through the connective tissue only.

General Features Of Connective Tissue

Connective tissue consists of two basic components: cells and matrix. The extracellular matrix itself is made up of two components, i.e., fibers and ground substance.

• Cells in the connective tissue are widely separated from each other because of the presence of an abundant extracellular matrix. Usually, the matrix consists of a gel-like ground substance in which fibers are embedded.
• In some, connective tissue matrices may be fluid, semi-fluid, gelatinous, fibrous, or calcified. The fibers and ground substance (matrix) are synthesized by the cells of connective tissue.
• A tissue can be designated as connective tissue only when it has all three components, i.e., ground substance, fibers, and cells.

1. Ground Substance

The ground substance is colorless, sol to gel in consistency, It is highly hydrated. Fibers are embedded in it. The cells of the connective tissues are surrounded by it.

• Ground substance supports cells and provides a medium through which substances are exchanged between blood and cells. It is made up of complex molecules of polysaccharides and proteins.
• It contains many types of proteoglycans, multi-adhesive glycoproteins (laminin and fibronectin), and glycosaminoglycans (dermatan sulfate, keratan sulfate, hyaluronic acid, etc).

Ground Substance Remember

• A tissue can be designated as connective tissue only when it has all three components, i.e., ground substance, fibers, and cells.
• The extracellular matrix provides mechanical and structural support for tissue and helps in extracellular communication.

2. Fibers

Fibers in the matrix provide strength and support to the connective tissue. Three different types of fibers may be found in the matrix: collagen, elastic, and reticular.

Collagen Fibres

Collagen fibers are the main fibers of the connective tissue. They are found in abundance in bone, cartilage, tendon, and ligament. These fibers are strong, and inelastic but flexible (20 to 300 nm in diameter).

• Collagen fibers mostly occur in bundles which may branch and anastomose with neighbouring bundles. However, an individual fiber does not branch.
• A bundle measures about 0.5 to 1 0 pm in diameter and is of indefinite length. A collagen flber shows faint transverse striations indicating that it is made up of smaller subunits.
• Collagen fibers run in bundles, which may branch and anastomose with neighboring bundles.
• Elastic fibers run singly and not in bundles. They branch and join together to form a network.
• Reticular fibers are much thinner than collagen fibers and form a branching network.
• Chemically, collagen fibers are made up of protein collagen that in turn is made of tropocollagen molecules. They are synthesized by fibroblasts.

At present, 28 different types of collagen fibers have been identified. They are designated as type 1, type 2, type 3, type 4 to 28, etc.

Further Details

Distribution of commonly occurring collagen fibers in the body

Following is a brief description of the most commonly occurring types of collagen fibers.

Type 1 Collagen

It is the most common of all the collagen types (90% of body collagen is type 1). These fibers show classical cross striations and are of large diameter.

These fibers are found in dense and loose connective tissue, bone, tendon, fascia aponeuroses, ligaments, skin, cornea, and dentine.

Type 2 Collagen

It consists of thin fibers showing faint cross striations. These types of fibers are found in hyaline cartilage, the vitreous of the eye, nucleus pulposus of the intervertebral disc.

Type 3 Collagen

These types of collagen form reticular fibers (see reticular fibers). It is present in connective tissue of organs (spleen, lung, liver, etc).

Type 4 Collagen

This type of collagen forms meshwork in the basal lamina (lamina densa) of epithelia. It is also present in the kidney, glomeruli, and lens capsule.

Type 5 Collagen

It is present in the placenta and is associated with type 1 collagen.

Type 7 Collagen

Present in anchoring fibrils that attach the basal lamina to the lamina reticularis.

Types 1,2 and 3 collagen can be seen by light microscope, while the remaining collagen types are detectable only by the use of specific antibodies.

Synthesis of Collagen Fibres

Fibroblasts synthesize fibers and ground substance components of connective tissue. Besides fibroblasts, many other cells of the body also synthesize collagen fibers.

• These cells are mesenchymal cells, perineurial cells, cementoblasts, odontoblasts, cartilage cells, and smooth muscle cells. Type 4 collagen, which is found in basal lamina, is synthesized by epithelial cells.
• The synthesis of collagen fibers by fibroblasts takes place in two different steps: intracellular and extracellular.

Synthesis of Collagen Fibres Remember

Synthesis of collagen fibers occurs both inside and outside the fibroblast.

Intracellular Synthesis

• With the help of mRNA, amino acids are arranged sequentially to form alpha polypeptide chains.
• These chains are then transferred to the lumen of the rough endoplasmic reticulum.
• The polypeptide chains undergo the following modifications in the rough endoplasmic reticulum:
  • Proline and lysine amino acids of the chain are converted to hydroxyproline and hydroxylysine.
  • Hydroxylysine combines with sugar groups.
  • Three polypeptide chains now form a helix (triple helix). However, both the terminal ends of these chains remain uncoiled.
  • This molecule is now called procollagen. [Vitamin C is necessary for the formation of procollagen. Therefore, the deficiency of vitamin C leads to non-healing of wounds, and the formation of bone is impaired.]
• These procollagen molecules now move from the rough endoplasmic reticulum to the Golgi complex. There occurs the packaging of soluble procollagen in secretory vesicles.
• From here these molecules are secreted in the extracellular space through secretory vesicles.

Extracellular Synthesis

• Various enzymes act on the terminal uncoiled portion of procollagen molecules and cleave it from the rest of the coiled portion. These enzymes (procollagen peptidase) are secreted by fibroblasts themselves.
• After cleavage of the procollagen molecule, the remaining molecule is now called a collagen molecule or tropocollagen molecule.
• The tropocollagen molecules aggregate in an orderly manner to form the collagen fibrils.
• The collagen fibrils assemble to form microscopically visible collagen fiber.

Extracellular Synthesis Remember

Collagen is not only synthesized by fibroblasts but also by many other cells of the body, i.e., chondroblasts, osteoblasts, epithelial cells resting on the basement membrane, mesenchymal cells, perineurial cells, cementoblasts, odontoblasts, and smooth muscle cells.

Elastic Fibres

The diameter of elastic fibers is 0. 1 to 0.2 pm. They run singly and branch to form a network in loose areolar tissue but are present in bundles in ligamentum flava and ligamentum nuchae.

• Chemically, elastic fibers consist of a protein called elastin. The fiber is surrounded by a glycoprotein called fibrillin. Fibrillin plays an important role in organizing elastin into fibers.
• Absence of fibrillin results in the formation of elastin sheets or lamellae, instead of elastic fibers, as found in blood vessels.
• Elastic fibers are strong and can be stretched up to 150% of their relaxed length. Their elasticity is due to the protein elastin. These fibers are stained dark brown with orcein and Verhoeffs methods.
• They are synthesized by fibroblasts and smooth muscle cells of blood vessels. Elastic fibers are mainly found in skin, blood vessels, and lung tissue.

Elastic Fibres Remember

• In relaxed conditions, the molecules of elastin are coiled and cross-linked to each other to form a network. The stretching leads to the uncoiling of these molecules leading to an increase in the length of the elastic ligament or membrane or lamella, etc.
• When the stretching force is withdrawn, the elastin molecules return to a relaxed condition (coiled condition).

Elastic Fibres Clinical Applications

Marfan Syndrome

• It is a disorder, which is due to the abnormal development of elastic fibers. Marfan’s syndrome is inherited as autosomal dominant and is due to a mutation of the fibrillin gene(FBN1).
• Tissues rich in elastic fibers, i.e., large arteries, I periosteum (a membrane covering the bone), and the ligaments that suspend the lens of the eye are weakened.
• This results in blurred vision due to displacement of the lens. Long bones become abnormally large and there occurs the weakening of the wall of the aorta. The weakened aorta may suddenly rupture leading to sudden death.

Comparison of the properties of connective tissue fibers

Reticular Fibres

• These are fine delicate strands (20-40 nm in diameter), that form a supportive network for many tissues.
• They do not run in bundles.
• Chemically, they consist of collagen (type 3) and have a coating of glycoprotein.
• They can be stained black by the silver impregnation method. Because of their affinity to silver salts, these fibers are called argvrophilic. These fibers are also PAS-positive.
• These fibers are also synthesized by fibroblasts. The other cells, which produce reticular fibers are reticular cells in lymphatic tissues, Schwann cells in endoneurium, and smooth muscle cells in blood vessels and the intestine.
• Reticular fibers provide support and strength and form a supporting framework around fat cells, nerve fibers, and smooth muscles. They also form the framework of the spleen, lymph nodes, bone marrow, liver, and glands.
• These fibers also help to form the basement membrane.

Reticular Fibres Remember

Reticular fibers are arranged in the form of a network (meshwork), which is necessary to provide support to glandular and epithelioid tissues.

3. Cells of Connective Tissue

The cells of connective tissue are of two different types: fixed cells and free cells. The fixed cells are long-lived. These include fibroblasts, myofibroblasts, pericytes, fat cells, mast cells, and pigment cells.

The free cells arc short-lived wandering cells that are continually replaced by cells of the blood. These cells include eosinophils, neutrophils, monocytes, lymphocytes, mast cells, and plasma cells.

Fibroblasts

• They are the most numerous connective tissue cells and are present in almost all types of connective tissues.
• Fibroblasts are large, fiat, spindle-shaped cells that have many branching processes.
• Fibroblasts are responsible for the synthesis of extracted lularmatrix (secretion of ground substance and all types of connective tissue fibers).
• Inactive fibroblasts are called fibrocytes. Active fibroblasts have a large quantity of basophilic cytoplasm and euchromatic nuclei.
• They become very active during wound repair and synthesize collagen fibers. Here, they lie parallel to the long axis of the fibers.

Fibroblasts Remember

Fibroblasts are the most numerous connective tissue cells and are involved in the synthesis of all types of connective tissue fibers and ground substances.

1. Active fibroblast
2. Inactive fibrocyte
3. Fat cell
4. Mast cell
5. Plasma cell
6. Lymphocyte and
7. Macrophage.

Myofibroblast

The myofibroblast is a cell showing features of both fibroblast and smooth muscle cells. In appearance, these cells resemble fibroblasts but contain actin and myosin filaments in large amounts.

• The myofibroblasts possess contractile properties and behave like smooth muscle cells. However, a myofibroblast differs from a smooth muscle cell in that it is not surrounded by basal lamina.
• Their activity is responsible for wound closure after tissue injury due to the contraction of the wound. They are also found in periodontal ligaments probably helping in tooth eruption.

Pericytes

Pericytes surround the endothelial cells of capillaries and venules. They are surrounded by their basal lamina, which fuses with the basal lamina of endothelium.

Pericytes show features of both endothelial and smooth muscle cells. They contain actin and myosin filaments and, thus are involved in contraction.

Fat Cells

Fat cells (adipose cells) synthesize and store large quantities of lipids. A fat cell is spherical. The nucleus is flattened and displaced to one side.

• The lipids occupy almost the whole of the cell, pushing the cytoplasm as a thin rim around it. The cell may occur singly as in loose areolar tissue or they may occur in groups as in adipose tissue.
• Fat cells are stained orange with Sudan 3 stain. In H and E, stains fat is dissolved, so cells appear empty (un-stained). Their appearance is like a signet ring. Fat cells are fully differentiated and do not undergo cell division.

Pigment Cells

Pigment cells are capable of synthesizing pigment melanin which is a dark brown pigment. These cells are called melanocytes.

These cells are found in the skin, iris, some areas of the brain, and the choroid. These cells are star-shaped with branching processes. In the skin, they protect the tissue from the harmful effects of ultraviolet rays.

Macrophages (histiocytes)

Macrophages develop from monocytes of blood. Macroph ages are capable of eating bacteria and cellular debris by the process of phagocytosis. They have irregular shapes with short branching projections.

• They have an indented nucleus. Macrophages are of two types: fixed macrophages and wandering macrophages. When the need arises macrophages may fuse to form giant cells (Langhans cells).
• The Langhans cells are very large and may contain up to 100 nuclei. They can engulf large foreign bodies.

Mast Cells

Mast cells are found mostly close to the blood vessels in connective tissue. These cells are small and oval. The nucleus is centrally placed and the cytoplasm contains many granules.

• These cytoplasmic granules take purple to red color when stained with toluidine blue stain, while the nucleus is stained blue. This kind of color reaction is called metachromasia.
• These granules contain heparin which acts as an anticoagulant of blood. Mast cells also release histamine that in turn causes contraction of smooth muscles (mainly of bronchioles) and dilates small blood vessels as part of allergic reaction.
• Leukotricnc C released by mast cells causes bronchospasm. Mast cells also produce TNF-a (tumor necrosis factor-a), interleukins, growth factors, and prostaglandins.
• The release of chemicals from mast cells promotes allergic reactions (For Example., immediate hypersensitivity reactions or anaphylactic shock).

Mast Cells Remember

Mast cells contain numerous granules in their cytoplasm These granules contain heparin, histamine, prostaglandin din, and many other chemicals involved in the inflammatory process.

Plasma Cells

Plasma cells arise from B-lymphocytes. They synthesize antibodies against antigens. Thus these cells are found more in connective tissue at the time of infection. Plasma cells are ovoid.

• The cytoplasm is basophilic due to the presence of abundant RER. There is a clear area of cytoplasm near the nucleus for the Golgi complex. The nucleus is round and eccentrically placed.
• The chromatin pattern is unique, giving it a cartwheel appearance. All the above features indicate that plasma cells are actively involved in protein (antibody) synthesis. The toxic antigen may be neutralized when it combines with the respective antibody.

Plasma Cells Remember

Plasma cells originate from B lymphocytes and synthesize antibodies.

White Blood Cells

Three different types of white blood cells are seen in connective tissues, i.e., lymphocytes, monocytes, and eosinophils. Lymphocytes play an important role in the defense of the body against microorganisms (bacteria etc.).

Monocytes act as macrophages, while eosinophils play an important role in allergic reactions. Thus all these cells function towards the defense of the body.

Plasma Cells Clinical Applications

Mast Cells and Anaphylactic Shock

Some persons when exposed to an antigen (substances foreign to the body, For Example. ( bee venom after a bee sting, some food, or certain drugs) becomes oversensitive to the antigen.

• This means that they produce antibodies as allergic reactions against antigens. These antibodies remain attached to the surface of mast cells.
• When they are exposed to the same antigen (bee venom, food, or drug) for the second time the antigen-antibody reaction takes place on the surface of the mast cells.
• This triggers the release of the contents of mast cell granules (i.e., heparin, histamine, and other chemicals) within a few minutes after the bee sting or taking the drug.
• Histamine causes contraction of smooth muscles (mainly of the bronchiole leading to wheezing and difficulty in breathing); the dilatation of blood vessels leading to the swelling of the face and sudden fall in blood pressure.
• This condition is called an anaphylactic shock. Anaphylactic shock is a serious condition and if not treated urgently may lead to death.

Functions Of Connective Tissue

The following main functions can be attributed to the connective tissue:

• Support: Connective tissue provides support to the epithelium, For Example., lamina propria.
• Strength: It provides tensile strength to those areas that are subjected to mechanical stress, For Example., the dermis of the skin, ligament retinaculum, etc.
• Storage: Fat cells store fat while ground substances store water, ions, and inorganic materials.
• Transport: Water, ions, and inorganic materials are transported from blood to the various tissues of the body through a connective tissue matrix.
• Packing: Connective tissues act as packing material as they fill spaces, For Example., loose connective tissue and adipose tissue. Connective tissue also forms capsules around organs.
• Repair: Connective tissue helps in wound healing.
• Defense: The cells of the connective tissue (plasma cells, lymphocytes, macrophages, monocytes, and eosinophils) function toward the defense of the body.

Integumentary System (Skin) Introduction

The skin is the outer covering of the body. The hair, sebaceous glands, nails and sweat glands are considered as derivatives or appendages of skin. Skin is the largest organ of the body. It consists of 16% of the body weight. The skin and its appendages constitute the integumentary system.

1. Skin Functions

• It acts as a protective shield for the body and protects us from injury, microorganisms, ultraviolet irradiations and chemical injuries.
• It provides a water barrier. Water cannot be absorbed or lost through superficial layers of epidermis, i.e., stratum corneum
• Sweat glands and unique vascular supply help in heat regulation. Sweat glands also excrete waste like urea
• Skin is an important sense organ for sensations like pain, touch, temperature and pressure
• It helps in the absorption of ultraviolet radiation from sun for the production of vitamin D

Skin Remember:

The skin along with its accessory structures is considered an important body system, which serves many important functions

2. Thick and Thin Skin

The skin on the surface of the palm and sole is thick. Here, the epidermis is much thicker than elsewhere. Thick skin is hairless skin in other places in the body, skin is thin and hairy, for details on thick and thin skin.

Differences between thin and thick skin:

Microscopic Structure Of Skin

The skin consists of two layers

1. Epidermis
2. Dermis

1. Epidermis:

It consists of stratified squamous (keratinized) epithelium. Following live layers can be distinct-guessed in thick skin from deep to superficial surface.

1.  Stratum hostile: It consists of a single layer of cuboidal cells, which are situated on the dermis. A thin basement membrane is situated between the stratum basale and der¬ mis. Basally located hemidesmosomes attach the cell to the basal lamina. Cells of this layer show high mitotic activity. The newly produced cells move towards the superficial layer
2. Stratum spinas am: It consists of several layers of polygonal cells, which are held together by desmosomes. These cells contain tonofilaments and tonofibrils in their cytoplasm. The presence of tonofibrils causes the cytoplasm to become eosinophilic. The artefact of fixation causes shrinkage of the cell membrane except at the desmosomes, giving the cell a spiny appearance. Because of this reason, this layer is called stratum spinosum
3. Stratumprumdusunr: This layer is made up of 3 5 layers of flattened polygonal cells. These cells are filled with keratohyalin granules
4. Stratum lucidum: This layer is seen only in thick skin. Cells in this layer are flattened, translucent, eosinophilic and without any organelles including the nucleus. These cells are filled with proteins called keratin and eleidin (a product of keratohyalin)
5. Stratum corneum: It is the most superficial layer of the epidermis. It is composed of structureless dehydrated dead cells. The interior of the cell is filled with keratin. The thickness of the stratum corneum is much higher in thick skin compared to thin skin. The superficial layer ot the stratum corneum is continuously sloughed oil. This process takes 20- 30 days

Stratum  Remember:

The appearance of the cells of stratum spinosum is due to their shrinkage during fixation in formaldehyde during the preparation of the slide. In living conditions, cells are almost rounded and without spines. Students should also remember that layer “stratum lucidum” is only present in thick skin. They should not try to find this layer while observing a slide of thin skin

2. Dermis

The dermis is predominantly made up of collagen bundles.It also contains elastic fibres, connective tissue cells, nerves, lymphatics and blood vessels. Dermis is usually divided into two layers

• Papillary layer: It is a narrow band of loose connective tissue in contact with the basement membrane of the stratum basale. This layer shows finger-like processes projecting into the undersurface of the epidermis. These projections are called as dermal papillae and serve to interlock the dermis and epidermis. The papillae contain type 3 collagen and elastic fibres, nerves, blood vessels and various types of connective tissue cells
• Reticular layer: The reticular layer of skin is an example of dense irregular connective tissue. It contains coarse bundles of type 1 collagen, thick elastic fibres, nerves, and blood vessels, but few connective tissue cells (fibroblasts, mast cells, lymphocytes, macrophages and fat cells

Skin Pigmentation: 

The colour of the Skin depends on the following factors:

• The pigment carotene of epidermal cells is responsible for the yellow colour of skin.
• Carotene is an exogenous or ange pigment taken up from food and concentrated in tissue containing fat
• The pigment melanin of epidermal cells gives a black colour to the skin
• The blood vessels of the dermis are responsible for the pink colour of the skin

The colour of the skin of an individual depends on a combination of the above factors.

Cells of Epidermis

The following types of cells are seen in the epidermis

• Keratinocytes: ‘Ninety per cent of cells in the epidermal layer arc epithelial cells, which are sometimes called keratinocytes (because of their capacity to produce protein keratin). The process of formation of keratin filaments is a continuous process, while the keratinocytes pass from stratum basale through st. spinosum and st. granulosum to the st. corneum
• Melanocytes:  The melanocytes are rounded cells with dendrite-like branches. These cells are present in the stratum basale. Melanocytes produce melanin pigment, which is responsible for the colour of skin.
  • They transfer melanin pigment to epidermal cells by “cytocrine secretion” (cell-to-cell transfer, i.e.„ it is a process in which keratinocytes phagocytosis the tip of melanocyte process) through their long dendrite-like branches.
  • These cells are derived from neural crest cells.
  • In white people, melanin is degraded by lysosomes, while in black people this pigment is more stable.
  • Melanin saves the nuclei from the ultraviolet rays of the sun
  • The melanin pigments arc present in the supranuclear region to protect the nucleus from ultraviolet rays from the sun

• Langerhans Cells: These cells are also called non-pigmented granular dendrocytes.
  • These cells are present in the stratum spinosum and normally constitute 2 to 4% of the epidermal cell population (their number may reach up to 800 per mm²).
  • They possess dendritic processes similar to melanocytes. Its nucleus is indented in many places and the cytoplasm contains rod-shaped granules.
  • Langerhans cells are phagocytic and belong to the mononuclear phagocytic system.
  • These cells protect the skin from foreign invasions, i.e., antigens, micro-organisms etc.
  • Therefore Langerhans cells are also known as antigen-presenting cells
• Merkel Cells: Merkel cells are sensory cells of the epidermis.
  • They are present in stratum basale and innervated by sensory nerves. Merkel cells are abundant in the fingertips, oral mucosa and hair follicles.
  • It is believed that Merkel cells function as mechanoreceptors. These cells are derived from the neural crest.

Cells of the epidermis Remember:

The cells of the epidermis are also known as keratinocytes The 90% of the cells of the epidermis are keratinocytes, while the remaining are melanocytes, Langerhans and Markel cells. Melanin saves the nuclei from the ultraviolet rays of the sun. Langerhans cells are known as antigen-presenting cells, while Merkel cells function as mechanoreceptors.

Skin Clinical Applications

• Albinism: Albinism is a kind of inborn error of metabolism. Here, melanocytes are unable to synthesize melanin pigments due to the absence of the enzyme tyrosinase. Thus, skin remains unprotected from sunlight and may develop skin cancers (basal and squamous cell carcinoma).
• Vitiligo: In vitiligo, there occurs the degeneration and disappearance of already existing melanocytes. This results in patchy de-pigmentation of the skin
• Warts: Warts are small round growths from the epidermis caused due to infection of epidermal cells by papillomaviruses. The virus invades skin cells and forces them to multiply, resulting in thickened areas of skin. Warts usually occur on hands and feet and mostly are harmless. Warts may also occur on the sole
• Skin Cancer:
  • Chronic exposure to excessive solar ultraviolet radiation may damage the DNA leading to basal cell carcinoma or malignant melanoma
  • In adults, most of the skin tumours are derived from basal cells, squamous cells of the stratum spinosum and melanocytes. They produce basal cell carcinoma, squamous cell carcinoma and melanomas, respectively
  • Malignant melanoma is an invasive tumour of melanocytes. This tumour may penetrate the basal lamina to enter the dermis. From here it may invade the blood and lymph vessels to gain wide distribution throughout the body

Question 1. Why does skin become wrinkled in old age?
Answer:

The suppleness of the skin, in young and adults, depends on the adequate presence of collagen and elastic fibre in the dermis. However, in old people there occurs the loss of these fibres due to decreased production. The overexposure to the sun also causes the degeneration of these connective tissue fibres. Both these conditions result in the wrinkling of the skin

Derivatives Of Skin

The following are the derivatives of the skin:

1. Nails
2. Hair
3. Sebaceous glands
4. Sweat glands and
5. Mammary glands

1. Nails

Various parts of nails are the inferior surface of the nail sits on a nail bed, which is made up of the stratum basale and stratum spinosum ofthe epidermis. The germinal matrix is the portion of the nail bed involved in the growth of the nail. The body and root ofthe nail are modified stratum corneum. The body of the nail corresponds to the upper cornified layer of the skin

2. Hair

A hair has a shaft, which projects above the surface of the skin, and a root which is enclosed by a hair follicle. The hair follicle is a tubular invagination that is partly epidermal and partly dermal origin

1. Structure of Shaft and Root of Hair: The structure of the shaft and root of hair consists of epidermal cells that are for the most part keratinized. These cells contain hard keratin and melanin granules. In a cross-section, various layers are seen such as the medulla, cortex and cuticle
2. Structure of Hair Follicle: The hair follicle is a tubular invagination of the epidermis and dermis in which the hair root resides Epithelial root sheath is derived from the epidermis. It has two parts
   1. Outer epithelial root sheath: This layer is the continuation of the skin and corresponds to the stratum basale and stratum spinosum
   2. Inner epithelial root sheath: This is a keratinized sheath that arises from cells in the hair matrix

Connective tissue root sheath:

• The connective tissue root sheath is derived from the dermis. It contains nerves vessels, etc. The arrector pili muscle (smooth muscle) extends from the papillary layer of the dermis to the connective tissue sheath surrounding the hair follicle. The contraction of the muscle depresses the skin and elevates the hair shaft and skin around the hair shaft. This leads to the
• Formation of “goosebumps” on the surface of skin. The Goosebumps are seen when a person is frightened (sympathetic overactivity) or chilled.

Hair bulb:

• The lower end of the hair follicle is expanded and this expansion is called a hair bulb. The cells of the hair bulb correspond to those of the stratum spinosum and form a germinal matrix or hair matrix. These cells are concerned with the growth ofthe hair.
• The cells of the germinative layer make up a single layer that rests directly on the dermis (the hair papilla). New cells are produced here and push older cells up. Cells acquire melanin and become keratinized.

Hair papilla (dermal papilla):

• The dermal papilla fills the indentation at the base ofthe hairbulb.
• It consists of highly cellular connective tissue, which is rich in cells, capillaries, and nerves and contains melanocytes.

Hair Remember: Hairs consist of keratinized cells that develop from hair follicles

3. Sebaceous Glands

These glands are present in the dermis in association with hair follicles.

• It secretes oily substances called sebum, which consists of cellular debris and various types of lipids.
• The sebum functions as a lubricant of the skin and hair shaft (prevents their dryness).
• The sebaceous gland is a solid mass of cells (thus no lumen is present).
• The basal cells undergo mitosis and polyhedral daughter cells are pushed towards the centre ofthe glands. The centrally located cells are degenerating.
• As the cells of sebaceous glands contain lipids they are either unstained or stained lightly with eosin in
• H&E preparation. The gland has a short and wide duct, which opens into a hair follicle The mode of secre¬ tion is holocrine, i.e.,
• The entire cell is lost in the process of secretion. The contraction of arrector pilgrim helps in the exudation of secretion’

Sebaceous Remember:

The sebaceous gland secretes sebum that functions as a lubricant of skin and hair shaft (prevents their dryness)

Sebaceous Clinical Applications

• Acne Vulgaris: At puberty, under the influence of sex hormones, sebaceous glands grow In sire and increase their production of sebum.
  • If the normal secretion of sebum is obstructed, then it may result in acne.
  • Acne Is the inflammation of sebaceous glands due to Infection by bacteria.
  • Acnes are small elevations of skin (pimples) that may contain pus and are usually confined to the face.
  • This occurs predominantly in teenagers. The disease is self-limiting and dis¬ appears after some time.

4. Sweat Glands

It is a simple (unbranched) tubular gland of epidermal origin. Sweat glands extend from the surface of the epidermis to the subcutaneous layer. It has two parts, i.e., the secretory portion and the excretory duct

The secretory portion is present in the deep dermis or subcutaneous tissue in the form of a twisted coil. The epithelium is simply cuboidal or columnar. It has three types of cells, i.e., clear cells, dark cells and myoepithelial cells In H and E preparation, clear cells look light due to abundant glycogen in their cytoplasm and dark cells contain large amounts Of RER.

Clear cells secrete watery components and dark cells secrete glycoprotein of sweat. The contractile myoepithelial cells are located between the base of secretory cells and basal lamina. Contraction of these cells helps in the expulsion of secretory products to Duct

The excretory duct is long and extends From the secretory portion to the surface of the epidermis. The epidermal portion is spiral and has no lining of its own it is bordered by epidermal cells of epidermis. The portion of duct lying in the dermis is lined by stratified cuboidal epithelium. These cells are involved in the reabsorption of sodium from the sweat. The secretion of the sweat gland is clear and watery and may contain electrolytes, urea lactic acid and some drugs etc, the mode of secretion is merocrine

Sweat glands are of two types:

1. Eccrine and
2. Apocrine

Eccrine sweat glands are widely distributed throughout the skin, but are present most densely in the skin of palms and soles (up to 450 glands per square centimetre) Apocrine glands are found in the skin ofaxilla, groin, areola of the breast, labia minora and perianal region.

• The secretion of eccrine glands is watery, while apocrine glands secrete viscous secretion containing protein and lipids ceruminous glands are modified apocrine sweat glands. These glands are present in the skin ofthe external acoustic meatus (external car canal) and produce a wax secretion.
• This secretion is called cerumen, which along with the hair of the ear canal provides a sticky barrier for foreign bodies. Sometimes, cerumen may accumulate in the ear canal and prevent the sound waves from reaching the tympanic membrane.
• The modified apocrine glands of eyelashes are called as glands of Moll Similarly, the modified sebaceous glands of fluid are known as Meibomian glands (tarsal glands). These glands are large and embedded in the tarsal plate

5. Mammary Glands

Mammary glands are modified (specialized) sweat glands that secrete milk in females, for histology of mammary glands.

Lymphatic System

The lymphatic system is also sometimes called as immune system. (Readers are advised to refer to the functions of the immune system from a textbook of physiology.)

Lymphatic System  system consists of the following structures:

• Lymphatic vessels: The thin-walled vessels collect the tissue fluid (lymph) and drain it into veins.
• Specific lymphatic organs: These are made up of accumulation of lymphatic tissue and are surrounded by capsule, e.g., lymph node, spleen and thymus
• Lymphatic tissue found within the tissues of other organs: Examples of this are lymphatic tissue found within the bone marrow, GI tract (tonsils, Peyer’s patches, appendix), urinary tract, respiratory tract, etc. These lymphatic tissues are not surrounded by a capsule

Question 1. What is lymph?
Answer: 

The tissue fluid drained by lymphatic vessels is called as lymph. It consists of tissue fluid, large molecules of proteins, fat droplets and particulate matters

Question 2. What is lymphatic tissue?
Answer:

It is a specialized form of connective tissue. The supporting framework of lymphatic tissue is a meshwork formed by reticular cells and reticular fibres. The spaces within the meshwork are occupied by a large number of lymphocytes. The other cells present in lymphatic tissue are plasma cells and macrophages. (In the thymus, the supporting framework is not formed by reticular cells and fibres, but by star-shaped epithelial cells called as epithelioreticular cells

Question 3. What are the General Functions of the Lymphatic Tissue?
Answer:

Defence of body. This is achieved by lymphocytes and macrophages, which protect the body from foreign cells (bacteria, viruses and cancer cells). Lymphocytes are capable of identifying foreign entities (antigens) at the molecular level and responding to them immuno-logically. Phagocytosis of foreign cells such as bacteria, viruses and cancer cells by macrophages. Lymphatic tissues are also involved in the production of lymphocytes and plasma cells.

Question 4. What are diffuse lymphatic tissue and lymphatic nodules?
Answer:

The accumulation of lymphatic tissue is seen in the mucous membrane of the gastrointestinal, respiratory, urinary and reproductive tracts. Here, lymphocytes are disposed of randomly beneath the epithelium. This kind of lymphatic tissue is called diffuse lymphatic tissue. These kinds of lymphatic tissues are also known as mucosa-associated lymphatic tissue (MALT). These collections of lymphatic tissues are located in areas where they come in direct contact with antigens and may initiate the immune response

A lymphatic nodule is a circumscribed concentration of lymphatic tissue (lymphocytes and related cells) that is not surrounded by a capsule ). The lymphatic nodules are found both in scattered lymphoid tissue infiltration ofthe connective tissues (as in lamina proper of appendix, tonsil, etc) as well as in the encapsulated lymphoid organs such as spleen and lymph nodes.

The lymphatic nodule may show a lighter stained area in the centre (germinal centre) surrounded by a darkly stained zone of densely packed small lymphocytes. The lighter staining of the germinal centre is because it contains large euchromatic lymphoblasts and plasmoblasts, which are involved in the production of lymphocytes and plasma cells. In a lymphatic nodule, the germinal centre develops only when a nodule is exposed to an antigen (for example, Infection, or foreign cells).

Lymphocytes Remember:

Lymphatic nodules are a circumscribed collection of lymphocytes within the meshwork of reticular cells. This kind of collection of lymphatic tissue is seen In the mucous membrane of gastrointestinal, respiratory, urinary and reproductive tracts

The Lymphatic System Acts as the Immune System:

It should be noted that various lymphatic organs and lymphatic tissues constitute the immune system. The cells of the immune system consist of lymphocytes and various supporting cells.

Classification of Lymphocytes:

Three different functional types of lymphocytes are found in the body, i.e., B lymphocytes, T lymphocytes and natural killer(NK) lymphocytes

1. T Lymphocytes (T cells)
   • These lymphocytes although originate in the bone marrow, get differentiated in the thymus gland, hence called as T lymphocytes
   • T lymphocytes constitute about 60-80% of total blood lymphocytes.
   • Three different types of lymphocytes are known, i.e., helper T, cytotoxic T and memory T cells
   • The T lymphocytes are involved in cell-mediated immunity in which, cytotoxic T lymphocytes bind to the surface of parasites and virally infected cells and kill them
2. B Lymphocytes (B Cells)
   • These cells originate and mature in the bone marrow.
   • B lymphocytes constitute about 20-30% of total circulating lymphocytes.
   • They are responsible for the production of various antibodies.
   • B lymphocytes are of two types, i.e., plasma cells (which produce antibodies) and B memory cells.
   • B lymphocytes are responsible for humoral immune response in which B lymphocyte produces antibodies, which combine with antigens to form antigen-antibody complexes.
   • These are removed by macrophages and neutrophils
   • B cells also express major histocompatibility complex 2 (MHCH) on their surface.
3. NK Cells
   1. These cells also originate in the bone marrow.
   2. They are genetically programmed to recognize those cells, which are viral Infected or tumour cells. Alter recogni¬ tion they kills these cells.
   3. NK cells constitute about 5- 10% of circulating lymphocytes

Question 5. How different types of lymphocytes are identified
Answer:

Various types of lymphocytes are similar in appearance, hence, cannot lie differentiated morphologically even under an electron microscope. However, both B and T lymphocytes are distinguished by immunocytochemical methods.

Different types of lymphocytes possess different types of unique molecules on the surface of their cell membrane. These molecules arc culled cluster ol’dilTcrenliation (CD) molecules. These CD molecules can be visualized by immuno-histochemical methods using monoclonal antibodies. This method has helped to identify various subtypes of lymphocytes. These CD markers are designated as numbers according to an international system

T cells express CD2, CD3, CD4, CD7 and CD8 markers. T cells expressing CD4 markers are called helper T cells. While T cells expressing CD8 markers are also known as cytotoxic T lymphocytes. B cells express CD9, CD19 CD20 and CD24 markers. Similarly, CD markers for NK cells are CD16, CD56 and CD94.

Supporting Cells of the Immune System:

The supporting cells of the immune system consist of reticular cells, macrophages, follicular dendritic cells, Langerhans cells and epithelioreticular cells

Lymphocytes Clinical Application

Acquired Immunodeficiency Syndrome (AIDS) The disease is caused due to infection of the human Immunodeficiency virus (HIV). The infection destroys the defence system (immune system) of the body. The virus binds to CD4 molecules of T helper lymphocytes and destroys their capability to fight infection, not only with HIV but also infections due to other viruses and bacteria.

The HIV multiply rapidly within the T lymphocytes and infects other lymphocytes so that their number is reduced significantly. As a result, the infected person ultimately becomes incapable of fighting against any bacteria or virus. Death usually occurs due to secondary infections.

Lymphatic Vessels

In addition to the blood vascular system, there exists a lymphatic system to assist in draining tissue fluid to the blood circulation. The lymphatic system consists of lymph vessels and lymph nodes. The tissue fluid leaves the blood capillaries at its arteriolar end and re-enters at its venule end The excess of tissue fluid, containing particulate matter colloidal material, is absorbed through lymphatic capillaries because these capillaries are more permeable than blood capillaries

Lymphatic vessels begin as a network of blind capillaries in the tissues of the body. The lymphatic capillaries unite to form progressively larger lymph vessels. The largest of these vessels are known as the thoracic duct and right lymphatic duct.

These vessels pour their lymph into venous blood at the root ofthe neck. While the lymph is travelling through lymphatic vessels, it passes through lymph nodes where it gets filtered. The foreign substances (antigens) being conveyed by the lymph are exposed to lymphocytes of lymph nodes, which ultimately leads to an immune response

Histology of Lymph Vessels

1. Lymph Capillaries:

The lymphatic capillary networks accompany the networks of blood capillaries. The histological structure of lymph capillaries is similar to blood capillaries. However, lymph capillaries are more dilated and irregular in cross-section compared to blood capillaries and lack a continuous basal lamina

Lymph Capillaries Remember:

In the lymph capillaries, endothelial cells overlap and act as a one-way valve, which permits only the passage of tissue fluid into lymphatic capillaries but prevents its escape.

2. Small size Lymph Vessels

Their histological structure is almost similar to lymph capillaries. but they are more dilated than capillaries A lymph vessel can be differentiated from a blood vessel by staining it with an immuno-histochemical method (using D2-40 as a marker). This stains only lymphatic endothelial lining

3. Medium Size Lymph Vessels

These vessels consist of three layers. In tunica intima. the endothelial cells rest on the basal lamina. In subendothelia! layer, connective tissue fibres are arranged longitudinally. In tunica media, the connective tissue and muscle fibres are circularly disposed. The tunica externa of lymph vessels is similar to that of veins.

4. Large Size Lymph Vessels:

Although the histological structure of large size lymph vessels resembles that of comparable size veins, it differs in two characteristics: the muscle tissue is more abundant than in veins and their tunicae are more difficult to distinguish. In the thoracic duct, muscle is arranged longitudinally

Lymphatic Organs

Lymphatic organs are made up of an accumulation of lymphatic tissue and are surrounded by capsules, i.e.,

1. Lymph nodes
2. Spleen and
3. Thymus

1. Lymph nodes

Lymph nodes are kidney-shaped structures measuring from a millimetre to one or two centimetres. Lymph nodes serve as filter of lymph and hence are placed in the pathway of lymphatic vessels. Several afferent lymphatic vessels enter the lymph node at its convex surface and a single lymph vessel leaves through the hilus as an efferent lymphatic vessel

The hilus also serves for the entry and exit of blood vessels and nerves  A section through the lymph node shows an outer darkly stained zone cortex and an inner medulla. The dark staining is due to densely packed lymphocytes in the cortex while the medulla is lightly stained because it contains fewer lymphocytes. The cortex has several lymph nodules, which may show a germinal centre (see above).

The Supporting Elements of Lymph Node:

• The connective tissue capsule surrounds the bean-shaped lymph node. It is made up of dense connective tissue (collagenous, elastic and a few reticular fibres).
• The trabeculae extend from the capsule into the substance ofthe lymph node
• Besides the capsule and trabeculae, the supporting elements in the organ are formed by reticular cells and reticular fibres, which form a meshwork throughout the cortex and medulla.
• Reticular cells synthesize reticular fibres (type 1 collagen) and ground substance. These cells also produce substance which attracts T and B lymphocytes and dendritic cells
• Dendritic cells, which are present in the parenchyma of lymph nodes are of bone marrow origin and they present the antigen t0 specific T cells
• This meshwork is not seen, in a histological section, as the spaces within this meshwork are occupied by densely packed iymph0cytes.
• This meshwork can be demonstrated by special staining

Passage of Lymph Through Lymph Node:

• Afferent lymphatic vessels pour their lymph into the subcapsular sinus, which is placed just under the capsule between the capsule and cortical lymphocytes.
• From here the lymph flows deep inside the cortex in the secular sinuses and reaches the medullary sinuses.
• The sinuses within the medulla are in the form of
• Interanastomosing channels between cords of lymphocytes.
• The medullary sinuses then drain into an efferent lymphatic vessel at the hilum through which lymph passes through the lymph node.
• The sinuses are lined by endothelium, but their wall allows passage of lymphocytes into and out of sinuses

The Parenchyma of Lymph Node:

The parenchyma of the lymph node is present in the form of the cortex and medulla. The cortex is darkly staining the outer portion of the node deep to the capsule. The cortex is further divided into the outer and deep cortex. Lymphocytes are the most numerous cells of parenchyma.

These lymphocytes’ outer cortex are organized in the form of nodules, which may be in the form of primary nodules (nodules is made up of small lymphocytes with heterochromatic nuclei with very little cytoplasm and thus is deeply stained) or secondary nodules (nodules possessing germinal centre,

Germinal centre stains lightly because there are few dark staining small lymphocytes, but there are more light staining large lymphocytes (lymphoblasts, with euchromatic nucleus and clear rim of cytoplasm), macrophages and young plasma cells.

The lymphocytes in the deep cortex are not organized in the form of nodules, but they are diffusely arranged. B lymphocytes are predominantly present in the outer cortex but T lymphocytes are present in the deep cortex

Cortex Medulla Remember:

The cortex of the medulla is rich in B lymphocytes, while the cortico-medullary junction of the lymph node is rich in T cells.

The medulla is the inner part ofthe node and consists of lymphocytic tissue arranged in the cords called as medullary cords.

Besides lymphocytes both the cortex and medulla also contain the following types of cells:

• Reticular cells: These cells along with reticular fibres serve as the framework of the lymph node.
• Plasma cells: B lymphocytes mature into antibody-producing plasma cells. These cells are mainly present in medullary cords
• Macrophages: These cells are mainly present in the medulla but are also common in the germinal centres. These cells are phagocytic, which hold and present antigens to lymphocytes to aid the immune response
• The antigen-presenting cells (APCs) like dendritic and follicular dendritic cells are also present in the lymph node.
• The Parenchyma of the cortex and medulla is traversed by blood vessels and lymph sinus both of which are lined by endothelial cells.

Functions of Lymph Node:

It serves as filter of lymph. Filtration occurs in two different ways, i.e., the reticular meshwork (meshwork formed by reticular fibres and reticular cells) obstructs The foreign bodies (antigens), while these foreign bodies are phagocytosed by macrophages.

The foreign bodies are presented to lymphocytes by reticular cells and macrophages, which aid in immunological reactions.

• Both B and T lymphocytes are produced by lymph nodes. Thus, both humoral and cellular immune functions oc¬ cur here.
• B lymphocytes mature to form plasma cells in lymph nodes, which produce antibodies.
• Re-circulation of B and T lymphocytes takes place here through lymph nodes, i.e., the circulating B and T lymphocytes may enter the lymph node through postcapillary venule and may pass in lymph via the efferent lymphatics, draining to the thoracic duct

Lymph node Remember:

The lymph node is an important site where foreign bodies are phagocytosed by macrophages. The immune response is initiated when foreign bodies are presented to lympho¬ cytes by reticular cells and macrophages.

The Circulation of Lymphocytes Through Lymph Node:

In addition to lymph, lymphocytes also circulate through the lymph node. The lymphocytes enter the lymph node from two different sources.

Few lymphocytes enter the lymph node through afferent lymphatic vessels and reach into the network of lym¬ phatic sinuses. From the sinus, they enter into the cortex of the lymph node where they engage in immunosurveillance. This lymphocyte now comes back to the sinuses and migrates out of the lymph node through efferent lymph vessels.

• Many lymphocytes enter the deep cortex lymph node through the wall of postcapillary venules.
• Postcapillary venules are specialized blood vessels because they are lined by cuboidal or columnar endothelial cells, hence, also called as high endothelial venules. These endothelial cells have receptors to identify specific types of lymphocytes.
• They signal lymphocytes to leave the postcapillary venule (by passing between endothelial cells) and migrate into the deep cortex of lymph node.

From here lymphocytes migrate in the entire cortex and after performing their function of immunosurveillance they mi¬grate in lymph sinuses to come out of the lymph node through efferent lymph vessels.

Lymph node Clinical Applications

Lymphadenitis (Enlargement of Lymph Nodes) Lymph nodes are located along the path of lymph ves¬ sels. Lymph flows from one node to the next. Lymphad¬ enitis is the name given to the enlargement of lymph nodes, which is usually secondary to the infection in the area of drainage of lymph.

The most common infection causing lymphadenitis is due to streptococcal and staphylococcal bacteria. Common symptoms of acute lymphadenitis are swollen and tender nodes, fever and gen¬ eral weakness. Lymph nodes are also enlarged secondary to cancer (malignancy) in the region of drainage

2. Spleen

The spleen, similar to the lymph node, is an encapsulated lymphatic organ. Lymph nodes filter the lymph while blood is filtered through the spleen (thus blood is monitored immunologically by the spleen). In humans, the spleen is a single large organ present in the upper abdomen and covered by the peritoneum.

A cut section through the spleen shows the substance of the spleen arranged in the form of limited pulp and red pulp. In a fresh section of the spleen (unstained), the white pulp is seen as circular grey areas scattered randomly throughout the substance of the spleen.

The white pulp is surrounded by red pulp. In the hematoxylin-stained section, the white pulp appears as basophilic due to the presence of small lymphocytes with heterochromatic nuclei. The red pulp appears red because it contains many blood sinuses filled with RBCs.

The Supporting Elements of Spleen:

The spleen is covered by a capsule made up of dense connective tissue. The capsule contains elastic fibres. From the capsule, trabeculae extend into the substance ofthe organ where they repeatedly divide to form a network. Small spaces within the trabecular network are occupied by the delicate meshwork formed by reticular cells and reticular fibres.

• Macrophages are also present in this delicate meshwork. The spaces of this meshwork are filled by lymphocytes, macrophages and blood cells.
• In red pulp, these cells are arranged in the form of cords, which itself forms a network
• These cords are called splenic cords. Spaces between cords are occupied by blood sinusoids.
• The hilus of the organ gives passage to the splenic artery, vein, nerves and efferent lymphatic vessels.
• The spleen has no afferent lymphatic vessels and efferent vessels originate in the white pulp through which lymphocytes go out of the spleen

Circulation of blood Through the Spleen:

• The splenic artery enters at hilum and its branches travel in the trabeculae.
• After repeated branching within trabeculae, the final branch enters the pulp where it is covered by the aggre¬ gation oflymphocytes.
• This peri-arteriolar lymphatic sheath is called the white pulp. At the centre of the white pulp is the central artery. The central artery then enters red pulp and terminates by branching into straight vessels that are called penicillin.
• Penicilli shows localized thickening called as an ellipsoid. Penicillin continues as arterial capillaries. The mode of flow of blood between arterial capillaries and splenic sinuses is yet not clear. Two different theories (open and closed circulation theories) have been proposed.
• According to the ‘closed circulation theory,’ arterial capillaries open directly into splenic sinuses that drain into tributaries of splenic veins that are present in trabeculae.

The splenic vein thus formed comes out from the hilus of the spleen.

According to the “open circulation theory,” the arterial capillaries open and pour their blood into splenic cords of pulp,

The blood cells from here (splenic cords) then enter the blood sinuses by passing between endothelial cells lining the wall of the sinus.

Pulps of Spleen:

The substance of the spleen consists of two different types of 2 1 pulp, i.e., white pulp and red pulp S The white pulp is the lymphatic tissue sheath that surrounds * the central artery. It contains lymphocytes and macrophages P in a reticular connective tissue meshwork.

This peri-area rial lymphatic tissue sheath may also contain lymphatic nodules with germinal centres. These nodules are called splenic & nodules or Malpighian corpuscles. Most of the lymphocytes in while pulp are T lymphocytes while nodules predominantly contain B lymphocytes.

The red pulp consists of a network of inter-anastomosing splenic cords. The splenic cords are made up of reticular cells and reticular fibres containing B and T lymphocytes, macrophages, plasma cells, RBCs and granulocytes. These splenic cords are also called “cords of Billroth.” In between the splenic cords, spaces are filled with branch¬ ing venous sinuses.

The macrophages and lymphocytes come in contact with the antigens present in circulating blood. This leads to the initiation of an immune response against blood-borne antigens

 Spleen Remember:

The periarterial lymphatic sheath of white pulp contains T cells, while the lymphoid nodule of white pulp contains B cells. The red pulp of the spleen consists of blood sinuses and splenic cords

Spleen Functions

• Filtration of blood.
• Immune response against antigens circulating in the blood. Site for production of B and T lymphocytes.
• Aged and abnormal RBCs are detained and destroyed in the red pulp by the macrophages of the splenic cord.
• Macrophages also remove bacteria by phagocytosis. Storage of blood.
• Formation of blood cells during fetal life.
• The spleen may enlarge secondary to malaria and leukaemias.
• The spleen is not an essential organ and can be surgically removed if required (as in the case of profuse bleeding alter injury to the spleen).

Spleen Clinical Application

Rupture of Spleen:

The spleen is a fragile organ and presents relatively superficial in the abdomen, therefore trauma to the spleen may lead to its rupture. As it is a highly vascular organ, rupture leads to rapid and massive bleeding, which may result in the death of a person soon after injury. In some cases, the spleen can be removed surgically without affecting the life of a person because its function of removal of aged red blood cells is taken over by macrophages present in the liver and bone marrow.

3. Thymus

It is an encapsulated lymphatic organ, which neither filters lymph (like a lymph node) nor blood (like a spleen). This is the only lymphatic organ, which is fully developed at birth, while organs such as lymph nodes, tonsils and spleen are underdeveloped and require the migration of B and T cells for their development.

Supporting Elements of Thymus:

Both the lobes of the thymus are completely covered by a thin layer of connective tissue capsule from which trabeculae extend into the substance of the organ. These trabeculae partially subdivide the lobe of the thymus into thousands of lobules, each of which has a cortical cap over inner medullary tissue.

• The medullary tissues are partly divided by the trabeculae, hence the medullary tissue of adjacent lobules are continuous with each other.
• Thus, the medulla is a continuous branching mass surrounded by the cortex. Through these trabeculae pass the blood vessels, nerves and lymphatics.
• The thymus has only efferent lymphatic
• The delicate supporting stroma of the organ, within a lobule, is formed by epithelial-reticular cells. These cells are stellate in shape and their cytoplasmic processes are joined with the processes of neighbouring cells with the help of desmosomes.
• Thus, epithelioreticular cells form a cytoplasmic reticulum within the thymus. This reticulum is different from the reticulum present in the spleen and lymph nodes.
• In the spleen and lymph node, the reticulum is formed with the help of reticular cells and reticular fibres.

The epithelioreticular cells envelope the thymic blood capillaries to form a “blood-thymic barrier.”It is believed that the blood-thymic barrier does not allow any antigen to enter the thymus where T lymphocytes are maturing, which otherwise may influence the development of T lymphocytes

MicroscopicStructure of Thymic Lobule:

Each lobule of the thymus is surrounded by connective tissue stroma and contains an outer cortex and inner medulla

The cortex contains a higher concentration oflympho¬ cytes than the medulla. The cortex is darkly stained because of densely packed small lymphocytes with heterochromatic nuclei.

The outer cortex receives stem cells from bone marrow”‘ which divide repeatedly to form small lymphocytes. These cells form the cellular framework for the entire 1 – These small, maturing lymphocytes then move towards the medulla. The mature lymphocytes leave the thymus via veins and lymphatics.

This entire process takes about 24 hrs The medulla stains lightly compared to the cortex because here lymphocytes are less densely packed. Because of this reason, epithelioreticular cells are more obvious. The ta i medulla also contains thymic or Hassall’s corpuscles. !lu; These are masses of concentrically arranged type 6 l epithelioreticular cells around a central degenerated homogeneous mass.

The Hassall’s corpuscles stain pink with acid |u dyes and their number increases with increasing age. The macrophages are found in large numbers both in the cortex and medulla. They engulf antigens and also remove the lymphocytes, which might have been produced in excess.

Thymic Remember:

In the thymic cortex, immunologically incompetent T cells acquire the immunological competency (site of maturation of T lymphocytes), while the medulla consists of all immune-competent T cells.

Thymic Epithelioreticular Cells:

Epithelioreticular cells provide a skeletal framework of the thymus, which is similar to the reticular cells and their associated fibres in the spleen and lymph node

Epithelioreticular cells show some features of epithelial cells such as the presence of intercellular junction and intermediate filaments. The thymus exhibits six different types of epithelioreticular cells, i.e., types 1,2,3,4, V and 6. Out of these six types, types 1,2 and 3 are present in the cortex and the remaining three in the medulla. It is believed that epithelioreticular cells are derived from the endoderm of third and fourth pharyngeal pouches.

The epithelioreticular cells provide an isolated and protective environment to developing (immature) lymphocytes.

The following functions can be attributed to various kinds of reticuloendothelial cells:

1. Type 1: They isolate lymphocytes from neighbouring connective tissue (capsule and trabeculae) and blood vessels of the cortex. These cells form occluding junctions with each other, thus isolating the thymic cortex from the remainder of the body
2. Type 2: These cells are present in mid cortex and form an isolated compartment for developing T cells
3. Types 3 & 4: These cells are present at the cortico-medullary junction. They form a functional barrier between the cortex and medulla
4. Type 5: These cells form the cellular framework for entire medulla lymphocytes. and form compartments for various groups of
5. Type 6: They form thymic corpuscles. Thymic cor¬ puscles are isolated masses of closely packed concentrically arranged type 6 epithelioreticular cells. They contain flattened nuclei and their number increases with the increase in age.

Though the function of the thymic corpuscle is not known it is believed that type 6 cells are involved in the production of interleukins (IL-4 and IL-7) that help in the differentiation and education of T lymphocytes. Some believe that thymic corpuscles are the site for the death ofT lymphocytes

Thymic (Hassall’s) Corpuscles:

The type 6 epithelioreticular cells form thymic corpuscles. These cells of the thymic corpuscle show keratohyalin granules, intermediate filaments and lipid droplets in their cytoplasm. The centre of the corpuscle shows the keratinization of epithelioreticular cells. Thymic corpuscles are functionally active multicellular components of the medulla that are capable f producing hormones like thymosin and thym opoietin.

Blood-Thymic Barrier:

Further Details The thymic barrier helps to protect the developing immature lymphocytes in the thymus from exposure to the external environment (antigens).

The following are the constituents of blood thymic barrier:

• Capillary endothelium with basal lamina and pericytes
• Perivascular connective tissue space containing macrophages
• TypeI epithelioreticular cells with their basal lamina

Thus, the perivascular connective tissue space is located between the basal laminar capillary endothelium and basal lamina ofepithelioreticular cells. The macrophages present in perivascular connective tissue phagocytose the antigenic molecules that may come out from the capillary lumen. Thus,the layers of the blood-thymus barrier provide necessary protection to the developing immature T lymphocytes and separate them from mature lymphocytes, which are circulating in the bloodstream

Blood Thymic Barrier Remember:

Blood-thymus barrier protects the developing T cells in the cortex form the macromolecules present in the blood

Thymus Functions:

• The thymus receives immunologically incompetent stem cells from bone marrow and provides the environment where they can divide and mature into T lymphocytes.
• The mature T lymphocytes are then carried from thymus, via blood, to the lymph nodes, spleen and other lymphatic tissues.
• T cells are important for both cellular and humoral immunological responses.
• Epithelioreticular cells secrete many factors.
• Thymopoietin induces T cell production and maturation.
• Thymosin supports T cell activities throughout the body.
• Thymus is essential till puberty. After puberty, the other lymphatic tissues ofbody are fully developed; hence, the thymus gets atrophied

Thymus Remember:

The thymus is a primary lymphoid organ where T lymphocytes are immunologically matured.

Thymus Clinical Application:

1. Myasthenia Gravis: Myasthenia gravis is a rare autoimmune disorder in which the immune system produces antibodies that attack and slowly destroy the receptors in muscles that receive nerve impulses.
   • As a result, the affected muscle fails to respond or responds only weakly to nerve impulses. The muscles of the throat, face and eye are most commonly affected.
   • The other muscles may also be affected.
   • The cause of the autoimmune disorder is not known, but about 70% of people suffering from this disorder have an abnormality of the thymus gland.
   • The most common abnormality of the thymus gland associated with this disorder is thymoma (a noncancerous tumour of the thymus
2. DiGeorge’s Syndrome: This syndrome is characterized by the congenital absence of the thymus gland.
   • The patient is unable to produce T lymphocytes, thus cell-mediated immune response is not functional.
   • Patients may die at a young age due to infection. Since the thymus is absent, the parathyroid gland also fails to develop.
   • In the absence of a parathyroid, death may be caused due to tetany.

Lymphatic Tissue In Other Organs

As stated earlier, the mucosa-associated lymphoid tissue (MALT) consists of localized lymphocyte infiltration and lymphoid nodules in the mucosa of GIT (tonsil, Peyer’s patches of intestine, appendix), respiratory (bronchus), re¬ productive and urinary tracts.

Palatine Tonsil:

• Palatine tonsils are collections of lymphoid tissue in the mucosa of oropharyngeal isthmus.
• Each tonsil consists of an aggregation of lymphatic nodules within the diffused lymphoid tissue
• This lymphoid tissue is present just beneath the stratified
  squamous epithelium ofthe oropharynx.
• This epithelium at places may go deep into the substance of the tonsil. This invagination epithelium within the lymphoid tissue is called as epithelial crypt.

Tonsil has only efferent lymphatic vessels. Infection of the tonsil is called tonsillitis

Tonsil Functions:

• Production of lymphocytes.
• Immunological responses against the antigens and organisms coming in contact with epithelium

Tonsil Clinical Application

Tonsillitis: The infection of the tonsil may be caused either by virus or by bacteria. The tonsillitis is common in children because their tonsils are exposed to infections for the first time. Tonsils become smaller with increasing age and hence tonsillitis is also less common in adults. Surgical removal of tonsils (tonsillectomy) is performed on children who have recurrent tonsillitis.

Circulatory System

The circulatory system consists of the heart and blood vessels.

1. The heart is a muscular pump, which facilitates the circulation of blood through all tissues and organs of the body by its rhythmic concentration.
2. Blood vessels form a closed system of tubes that carry blood away from the heart to the tissues ofthe body and then return it to the heart.
3. Blood vessels consist of arteries capillaries and veins.
4. Arteries are blood vessels that carry blood from the heart to calories
5. The capillaries are thin-walled blood vessels arranged in an .work within the tissue. The exchange of substances between blood and tissue (distribution of oxygen and nutrients to the tissues and collection of carbon dioxide and other waste products from them) takes place through the walls of capillaries.
6. The veins return blood to the heart

The heart and blood vessels are all lined on the inner surface of the heart face by endothelial cells (simple squamous cells). For the histological structure of heart and the structure of the myocardium (heart muscles) .

The three layers of the heart (epicardium, myocardium and endocardium) are homologous to three layers of blood vessels (tunica intima, tunica media and tunica adventitia, see below

Circulatory system Remember:

The circulatory system consists of the heart and blood vessels, hence sometimes also known as the cardiovascular system. It consists of two kinds of circulation, i.e., pulmonary circulation and systemic circulation. Pulmonary circulation carries blood to the lungs, while systemic circula¬ tion carries blood to various tissues of the body

General Structure Of Blood Vessels

Three layers of tissue constitute the wall of a typical blood vessels

1. Tunica intima: It consists of a single layer of squamous endothelial cells and underlying sub-endothelial connective tissue
2. Tunica media: It consists of smooth muscle cells arranged concentrically around the lumen of the vessels
3. Tunica adventitia: It mostly consists of connective tissue arranged parallel to the long-axis lumen of the vessel

 Blood vessels Remember:

The tunica adventitia of blood vessels, which Itself consists of connective tissue, blonds with the surrounding connective tissue. The histological structure of various kinds of blood vessels is described below in detail.

Arteries

As stated earlier, arteries are vessels, which conduct blood from the heart to capillaries. Arteries branch repeatedly between the largest arteries to the capillary plexus. Because of this repeated branching, the total cross-sectional area of the vascular system increases to 800 times that of the aorta. With an increase in the branching, there is a gradual decrease in the rate of blood flow. This slow flow provides ample time for the exchange of substances through capillaries.

General Structure of Arteries

The wall of every artery passes following three characteristic layers

1.  Tunica intima:  It is the innermost layer. It consists of the following four components
   1. The endothelium is made up of simple squamous epithelium that faces the lumen and comes in contact with blood
   2. Basal lamina
   3. Subendothelial connective tissue is made up of cate connective tissue.
   4. Internal elastic lamina is made up of a layer of elastic material.
2. Tunica media:  The tunica media Is the Intermediate layer surrounding the tunica Intlma, ft Is usually the thickest layer and consists of elastic fibres and smooth muscle cells In varying proportions depending on the size of the artery see below).
   1. The smooth muscle cells and elastic fibres are arranged circularly or helically).
   2. The tunica media Is separated from tunica adventitia by external elastic lamina composed of elastic fibres.
   3. The Internal elastic lamina Is fenestrated permitting the diffusion of substance Into deeper regions of the arterial v/aJJ to nourish the cells,
3. Tunica adventitia (external):
   1. This Is the outer coat of an artery and is composed mainly of connective tissue elements (predominantly of collagen fibres and connec¬ tissue cells).
   2. The collagen fibres in adventitia run longitudinally

Arteries Clinical Application

Question 1. What are the functions of endothelial cells?
Answer:

Besides providing the smooth surface in the lumen of blood vessels for free flow of blood, endothelial cells also perform

The following important functions:

1.  Secretion:  They secrete type II, IV and V collagen, lamin, endothelin (a vasoconstrictor substance), nitric oxide and von Willebrand factor. The Von Willebrand factor facilitates the coagulation of platelets during clot formation.
2. Site for storage of enzymes: They possess many membrane-bound enzymes. The angiotensin-converting enzyme converts angiotensin I to angiotensin II for the regulation of blood pressure. Endothelial cells also bind lipoprotein lipase, which breaks the lipoproteins. Enzymes of endothelial cells inactivate serotonin, bradykinin, prostaglandins, thrombin and noradrenaline.

Arteries Of  Remember:

Endothelial cells perform many functions, which are necessary for the functional and structural integrity of vessel wall itself

Arteries Of  Classification

Arteries are classified into three types

1. Elastic (conducting) arteries
2. Muscular (distributing) arteries
3. Arterioles

This classification is based on the diameter of arteries, thickness of the wall and dominant component of their tunica media (elastic material or muscle fibres). There is always a gradual change seen from large-size elastic arteries to muscular arteries to arterioles.

1. Elastic Arteries:

These are also called conducting vessels as their main function is to conduct the blood from the heart to the muscular arteries. Examples of these arteries are large-size arteries like the aorta, pulmonary trunk and their main branches,i.e., brachiocephalic, common carotid, subclavian and common iliac.

They are called as elastic arteries because tunica media in these arteries is predominantly made up of elastic fibres , Usually the diameter ofan elastic artery is more than 1 cm.

1. TunicaIntima:
   • Endothelium: It is a simple squamous epithelium resting on basal lamina. These flat cells are elongated and oriented with their long axis to the direction of blood flow.
   • Subendothelial layer: It consists of connective tissue. This layer contains collagen and elastic fibres, smooth muscle cells, fibroblasts and macrophages.
   • The internal elastic membrane: In large-size elastic arteries, this layer is not visible because it becomes difficult to differentiate it from many elastic layers present in tunica media
2. Tunica Media:
   • It is the thickest of three layers of elastic arteries. Tunica media contains a high proportion of elastic fibres in the form of sheets or lamellae, which are arranged as concentric fenestrated sheets.
   • In between elastic lamellae are layers of smooth muscle cells, type collagenous fibres and ground substance. Compared to elastic layers, smooth muscle lay¬ ers are thin and circularly oriented.
   • There are about 50 lamellae of elastic material in the human aorta. In histological sections, internal and external elastic laminae are not differentiated from other elastic lamellae of tunica media. Smooth muscle cells of media are considered to produce elastin and collagen.
3. Tunica Adventitia:
   • This layer is made up of a connective tissue layer. It is rela¬ tively thin and contains longitudinally running collagen fibres. There is also a loose network of elastic fibres.
   • It contains fibroblasts, macrophages and mast cells. As the media is very thick, the diffusion of metabolites from the lumen of large-sized arteries is inadequate.
   • Hence, tunica adventitia contains blood vessels (vasa vasorum), which supply blood to adventitia and outer media, while inner media and intima are supplied by blood flowing through the lumen of the artery.
   • Adventitia also contains nerve bundles and lymph vessels.

Elastic Arteries Remember:

Tunica media of elastic arteries is predominantly composed of concentric layers of fenestrated elastic membranes. Smooth muscle cells are less abundant in this type of conducting arteries

Elastic Arteries Functions:

1. Elastic arteries conduct the blood from the heart to medium size (muscular) arteries.
2. Their elastic recoil is responsible for the continuous flow of blood through arteries

Elastic Recoil:

The large arteries (elastic arteries) nearest the heart are subjected to the greatest contractile forces and therefore possess greaterproportion of elastic tissue in tunica media. As the blood is pumped from the heart into large arteries, their elastic walls distend, accommodating the surge of blood

The distention of the elastic wall accumulates the potential energy. During the diastole (relaxation of ventricles), the distended arteries come back to their original size because of elastic recoil.

This elastic recoil converts the potential energy (stored energy) in the vessel into the kinetic energy of the blood. The blood continues to move through the arteries even during diastole because recoil acts as an additional force that helps the blood to flow continuously

2. Muscular Arteries:

These are also known as medium-sized arteries. Usually, the diameter of the lumen of the muscular artery is 2-10 mm. As these arteries regulate the flow of blood to an organ or tissue these are also called distributing arteries (For example, brachial, femoral, ulnar, radial, renal, etc).

With the gradual change of elastic arteries to muscular arteries, the elastic material decreases and smooth muscle cell becomes the main constituent of tunica media. Muscular arteries are of smaller diameter than the elastic arteries. The internal elas¬tic lamina (membrane) is visible

1. TunicaIntima: The layers of endothelial cells and basal lamina are same as in large elastic arteries.  The subendothelial connective tissue is much less or even absent. In the histological section, the internal elastic lamina is prominent and seen as a wavy structure due to the contraction of smooth muscle in tunica media(after death due to rigormortis).  The internal elastic lamina is clearly visible only in muscular arteries
2. Tunica Media: Smooth muscle cells are predominantly present in the form of circumferentially or spirally oriented layers.  The 75% mass of media is formed by smooth muscle cells and associated reticular fibres.  Media also contains type collag¬enous fibres and relatively little elastic material. Each smooth muscle cell is surrounded by its basal lamina.  Gap junctions are present between adjacent muscle cells for coordinated contraction
3. Tunica Adventitia: It is made up of connective tissue. Although it is thicker than the tunica adventitia of elastic arteries, both are almost similar histologically.

Muscular Arteries Remember:

Tunica media of muscular arteries is the thickest layer of the vessel wall and predominantly consists of helically arranged smooth muscle cells

Muscular Arteries Functions:

• The smooth muscle of the tunica media of the muscular artery can alter the size of its lumen by contraction or relaxation.
• In this way, muscular arteries are capable of regulating the How of blood as per cent of regions supplied by them.
• The small size muscular lyrics are of 1- 2 mm in diameter having 8-10 layers of smooth muscle cells in the tunica media

Some Important Differences Between Elastic and MuscularArteries:

• The diameter of the lumen of the elastic artery is much more compared to the thickness of its wall. On the other hand, the thickness of the wall of the muscular artery is rela¬tively more compared to the diameter of its lumen.
• The internal and external elastic laminae are visible in the muscular arteries, while they are will-defined in the elastic artery because the media predominantly contains elastic laminae, thus internal and external elastic laminae are difficult to distinguish.
• The tunica adventitia of the elastic artery is relatively thin compared to the muscular artery

3. Arterioles:

Small arteries having a size less than 100 μm are classified as arterioles. They terminate into the capillary network. The precapillary terminal arterioles may have a diameter as less as 12 μm noon.

Comparison between various types of arteries:

1. TunicaIntima: The tunica intima is formed by endothelial cells resting on the basal lamina, which in turn is supported by thin layer of subendothelial connective tissue. There is an absence of internal and external elastic. lamina in most of the arterioles
2. Tunica media: It consists of a thin layer of circularly arranged smooth muscle cells. In large-size arterioles, there may be 2 or 3 layers of smooth muscle cells while in terminal arterioles there is only one layer of smooth muscle cells. In terminal arteries, these smooth muscle cells may act as precapillary 1 2 t sphincter, which regulates the flow of blood through the capillary network depending on the metabolic needs ofthe tissue
3. Tunica Adventitia: The tunica adventitia is thin and well-defined and consists of collagen fibres and occasional fibroblasts. Sometimes in very small arteriole adventitia is not visible

Arterioles Remember:

Although the arterioles are less than 0.1 mm (100 millimicrons) they consist of all three vascular coats

Arterioles Functions:

• Arterioles regulate the blood flow through capillaries.
• The change in the diameter of arterioles (vasoconstriction or dilatation) can also significantly alter blood pressure.
• Arterioles that supply the blood to the capillaries are called as metarterioles, the smooth muscle layer is not continuous but individual muscle cells are placed at intervals. Their contraction controls the blood flow into the capillary bed.

Metarterioles Remember:

Smooth muscles of metarterioles may act as a precapillary sphincter, which controls the blood flow in the capillary bed (i.e., dilation increases the blood flow, while constriction reduces it). This vascular resistance also controls the systemic arterial blood pressure

Arteriosclerosis Clinical Applications

Arteriosclerosis:

• It is an age-related change of arteries and is usually seen after middle age.
• There is generalized slow thickening of the intima of arteries.
• This is due to an increase in collagen and the accumulation of lipids in the intima.
• This leads to the diffuse narrowing of the lumen of blood vessels.

Atherosclerosis:

• It is a pathological condition. Here, there is a patchy accumulation of lipid, fibrous tissue and macrophages in tunica intima.
• The elevated plaque of the intima leads to the narrowing of the arterial lumen. Formation of blood [clots on the plaque may occlude the lumen.
• When this occurs in the coronary artery it may lead to myocardial infarction (heart attack) and when it occurs in the brain it may lead to cerebral thrombosis (stroke)

Hypertension or High Blood Pressure:

• When the systolic blood pressure exceeds more than 140 mmHg and the diastolic more than 90 mmHg for a prolonged period, then the condition is known as high blood pressure or hypertension.
• From middle age onwards, this condition results mainly due to increased vascular resistance. This increased resistance is due to the narrowing of the lumen of small arteries and arterioles.
• This narrowing may be secondary to the increase in the amount of smooth muscle in the wall or due to the active contraction of the smooth muscle.
• The amount of smooth muscle increases because of the multiplication of preexisting smooth muscle cells.

Aneurysm:

• It is a sac-like dilatation of the wall of an artery. It occurs due to weakness in the wall of the artery resulting from the replacement of elastic fibres by collagen fibres.
• The disease is usually seen in the aorta and carotid vessels in old age where it may be associated with syphilis, Marfan syndrome, Ehlers-Danlos syndrome (both syndromes are associated with connective tissue disorders) and atherosclerosis.
• If not detected and repaired early, death may result due to rupture leading to rapid loss of massive blood.

Capillaries

Capillaries are thin-walled endothelial-lined microscopic vessels that connect arterioles and venules. They form an extensive network of vessels almost in every tissue of the body. The diameter of the capillary is between 5-10 μm and the length is approximately around 50 μm.

As the diameter of erythrocytes is about 7 μm, they pass through the lumen of the capillary, one at a time. While they are passing through the narrow lumen (5-8 μm) there occurs deformation in their shape. The surface area of all capillaries of the human body is roughly 1,000 square meters. The total length of capillaries in the body is about 40,000 miles

Capillaries Remember:

The diameter of capillaries is sometimes smaller than the diameter of an RBC, so red blood cells range themselves in a file and also fold on themselves to pass through the capillary.

Microcirculation:

The flow of blood through a capillary is called microcirculation. The capillaries consist of a single layer of extremely thin endothelial cells with a basal lamina supported by a loose network of reticular fibres. The lumen of the capillary may be lined by only one cell or by portions of two or even three cells. These endothelial cells are elongated in the direction of blood flow. The margins of endothelial cells are joined with tight junctions (zonulae occludens).

Sometimes, discontinuities in the cell junction may be seen through which fluid or leucocytes may pass. The thin margin of cells may also overlap. In some capillaries, pericytes are found in association with endothelium and embedded within the basal lamina of endothelium.

Pericytes possess long oval euchromatic nuclei and several peripheral processes that clasp the capillary wall. Pericytes are unspecialized cells capable of differentiating into fibroblasts or smooth muscle cells as per the need

There is no tunica media or adventitial layers in capillaries:

Capillaries are of three different types

1. Continuous capillaries
2. Fenestrated capillaries
3. Sinusoids

Layers in capillaries Remember:

Capillaries consist of a single layer of endothelial cells resting on basal lamina. Tunica media and tunica adventitia both are absent in capillaries

The speed of flow of blood through capillaries is very slow. Thus, enough time becomes available for the exchange between blood and tissue

1. Continuous Capillaries:

In the continuous type of capillaries, the plasma membrane of endothelial cells forms a continuous tube. The peripheral portions of the endothelial cells are very thin. Endothelial cells are held together by tight junctions. The basement membrane surrounds the endothelium.

The main feature of the continuous capillary is the presence of pinocytic vesicles that indicate the mode of transepithelial transport (through the cytoplasm of epithelial cells). These types of capillaries are found in tissues like muscle, brain, connective tissues, skin and lung. Sometimes this kind of capillary is also called somatic capillary

2. Fenestrated Capillaries:

In the fenestrated type of capillaries, the endothelial cells have many circular pores ranging from 50 to 100 nm in diameter. Apore is usually closed by thin diaphragm, which is thinner than plasma membrane and resembles in appear¬ ance thin basal lamina. The diffusion of substances takes place through the diaphragm.

This type of capillary is found in the pancreas, endocrine glands, intestinal villi, choroid plexus and ciliary processes of the eye. This kind of capillary is also called as visceral capillary. The capillaries of renal glomeruli have pores, which are not closed by the diaphragm. However, they have unusually thick basal lamina.

3. Sinusoids:

Sinusoids are special kinds of capillaries that are large (about 30-40 pm in diameter) and irregular in shape. Because of this, the flow of blood is sluggish which allows sufficient time for the exchange of substances between blood and tissue fluid.

Large pores or slits are seen in endothelial cells, which are large pores or slits are seen in endothelial cells, which are not closed by diaphragms. Blood and tissue fluid can easily diffuse through these pores.

A basal lamina may or may not be found over these endothelial discontinuities(slit or pores) thus increasing the exchange between blood and tissue. Sinusoids may also contain specialized lining cells that are adapted to the special function of tissue, i.e. sinusoids in the liver contain phagocytic cells (Kupffer’s cells) which remove bacteria and other foreign particles from the blood. The sinusoidal capillaries or sinusoids are found in the liver, bone marrow, spleen, anterior pituitary gland, parathyroid and adrenal medulla.

Capillaries Functions 

• The exchange of gases, fluid and molecules between blood and tissue takes place through the walls of capillaries.
• In the continuous capillaries, the mechanism of exchange across the capillary wall is due to transcytosis (through cytoplasm) while in fenestrated capillaries the exchange takes place through diffusion of substances across the diaphragm, which is 100 times more rapid than across continuous capillaries.
• When the need arises endothelin is secreted by capillary endothelium and reaches the muscle cells of blood vessels where it helps in the contraction of smooth muscle leading to an increase in blood pressure. Prostacyclin, a potent vasodilator, is also released by capillaries. NO and O₂ tension are other vasodilating agents

Differences between the three types of capillaries:

Veins

Veins are classified as large, medium and small-sized veins. Small size veins arc also known as venules. which are further classified as post-capillary and muscular venules. Though the large and medium-sized veins have the same three layers (i.e., tunica intima, media and adventitia) as seen in large and medium-sized arteries, these layers are not well defined in veins.

The large and medium veins and corresponding arteries usually travel together and thus can be compared in histological sections. For comparison of arteries and veins

Differences between artery and vein:

Veins Remember:

Veins are classified based on their size (diameter) and the thickness of their wall

1. Large veins

Large veins have the following three layers

1. TunicaIntima: It consists of endothelial cells resting on the basal lamina, itself is supported by a small amount ofsubcndothclial con¬nective tissue and a few smooth muscle cells
2. Tunica Media: It consists of smooth muscle cells, collagenous fibres and fibroblasts. Smooth muscle cells are usually arranged longitudinally and circularly. Tunica media in veins is thin compared to that of arteries. As smooth muscles are present both in intima and media, it becomes difficult to distinguish the boundary between the two
3. Tunica Adventitia: This layer is always thicker than media and contains smooth muscle cells, which arc oricntcii longitudinally. Adventitia also contains bundles of collagen elastic fibres and fibroblasts. The thin-walled large veins are protected from stretching (because of movements of the diaphragm) by longitudinally oriented smooth muscles and elastic fibres

2. Medium Veins

Medium-sized veins will show all three layers as described for large-size veins. However, it becomes gradually difficult to distinguish all three layers with decreasing si/e of medium-sized veins. The tunica intima consists of little or no subendothelial connective tissue. Media consists of a few layers of smooth muscle and associated collagen and elas¬ tic fibres. The adventitia is typically thicker than media and consists of collagen and elastic fibres

As stated earlier, veins are accompanied by arteries of corresponding size and it would be easier to identify first a medium size artery, which would help to identify the medium vein lying close to it in a histological section.

3. Small Veins or Venules

Small size veins are also known as venules that are of two different types, i.e., postcapillary venules and muscular venules.

Two to three capillaries converge to form postcapillary venules, which are the smallest veins (10-0.5 νm). These are lined by endothelium, basal lamina and pericytes. Pericytes are branching cells, which may be outside the basal lamina or sometimes enclosed by basal lamina. The postcapillary venules possess special permeability (diffusion of fluid and white blood cells into surrounding tissue and absorption from tissue into venules)

Comparison between various types of veins:

Veins Clinical Application

Varicose Veins:

Varicose veins are abnormally enlarged tortuous veins seen in the legs of an old person. The varicose veins result due to the failure of valves, which help the blood flow in the antigravity direction. Sometimes, varicose veins may also be caused due to loss of muscle tone and degeneration of vessel walls.

These veins may also result from prolonged standing as in case of the washerman remaining standing while washing the clothes. Two other sites where varicose veins are common are the oesophagus and anal canal where it is known as haemorrhoids (or piles)

The larger venules are called muscular venules because of the presence of one or two layers of smooth muscle cells outside the tunica intima. These muscle layers constitute tunica media that is absent in postcapillary venules. The tunica adventitia is thicker than the tunica media

Blood Supply And Nerve Supply To Blood Vessels

1. Blood supply to blood vessels:

“Vasa vasorum” is the name given to the small arteries and veins that enter the vessel wall and branch profusely in tunica adventitia and

Outer part of tunica media of size vessels. They provide nutrition and remove wastes from the outer part of the vessels as the inner part of the wall is directly supplied by nutrients from the lumen of the vessel

2. Nerve supply of vessels:

The sympathetic part ofthe autonomic nerves is vasomotor to the smooth muscle cells of the blood vessels. Their stimulation leads to the release of norepinephrine, which causes the constriction ofthe smooth muscle cells of tunica media (vasoconstriction). Arteries that supply skeletal muscles also receive parasympathetic (cholinergic) nerves, which are responsible for vasodilation.

The Cell Structure

The Light and Electron Microscopic Structure of Cell

A cell is a basic structural unit of any living organism and is involved in vital functions to maintain its life. Though the various cells of the body differ in their structure and function, most of them have many common structural components.

They all are surrounded by plasma membranes, possess organelles, and produce macromolecules and energy. This chapter will deal with the common structure of a cell.

The Cell

A cell is bound by the cell membrane. The cell membrane encloses the cytoplasm and nucleus. The cell varies in shape (flat, cuboidal, columnar, pyramidal, fusiform, multipolar, etc) and size (5-50 μm).

We shall study the structure of a cell under the following three headings:

• Cell membrane
• Cytoplasm
• Nucleus

The Cell Remember

A cell is a structural and functional unit of any living organ¬ ism. It is the smallest and independently living part of a living organism. It varies in shape (flat, cuboidal, columnar, pyramidal, fusiform, multipolar, etc) and size (usually 5-50 μm).

Cell Membrane

The cell membrane is also known as the plasma membrane or plasmalemma. It forms the boundary of the cell and acts as a barrier between the cytoplasm and the surrounding environment of the cell.

• The cytoplasm contains many organelles that are also made up of membranes (For example, endoplasmic reticulum, Golgi apparatus, mitochondria. etc).
• Although the cell membrane and membranes surrounding cytoplasmic organelles differ slightly in their thickness and protein contents, they all have the same basic molecular organization and are also known as unit membranes. The cell membrane is made up of lipids, proteins, and carbohydrates.

Structure Of Cell Membrane

• The total thickness of the cell membrane is just about 8-10 nm. Hence, it is not visible with a light microscope.
• When viewed under an electron microscope the plasma membrane seems to be made up of three layers i.e., trilaminar.
• The trilaminate appearance is because two dark lines are separated by a clear (unstained) intermediate zone.
• This appearance is due to the arrangement of phospholipid molecules in two different layers.
• A phospholipid molecule has a head and a tail end. These molecules are so arranged that their head ends face the outer and inner surface of the membrane while their tail ends face each other.

Cell Membrane Remember

The cell membrane (plasma membrane) is about 8-10 μm in thickness. It is visible only under an electron microscope and seems to be made up of three layers (trilaminate).

The trilaminate appearance of the membrane is because the heads of the phospholipid molecules form the dark-staining part of the membrane while the light-staining intermediate zone is formed by the tails of the molecules.

• Besides the molecules of phospholipids, the membrane also contains several types of proteins in the form of globular masses. These proteins are present within the thickness of the cell membrane or may project through its outer or inner surfaces.
• Many integral proteins pass through the entire thickness of the membrane (transmembrane proteins).
• On the outer surface of the cell membrane, carbohydrates may attach to proteins forming glycoproteins. Although at certain places carbohydrates may also attach to lipid-forming glycolipids.
• Thus, the carbohydrates are only present on the outer surface of the plasma membrane. The coat of glycoprotein and glycolipid, on the outer surface of the plasma membrane is called a cell coat (glycocalyx).
• The glycocalyx is formed by carbohydrate chains and protects the cell from interaction with inappropriate proteins, chemicals, and physical injuries.

The cell membrane is composed of lipids as well as proteins. Protein molecules are about half of the total mass of the membrane, i.e., lipids and proteins are usually in 1:1 proportion by weight.

• Besides phospholipids and glycolipids, the plasma membrane also contains cholesterol that is present among the fatty acid tails of phospholipids.
• The lipid bilayer behaves like a fluid within which the globular proteins are free to move laterally if not attached to filaments in the underlying cytoplasm.
• Neighboring lipid molecules may exchange places about 10 million times per second and may wander completely around a cell in a few minutes. The globular proteins of the cell membrane can float like icebergs in the sea of phospholipids.

The above description of the molecular organization of cell membrane is called as “fluid mosaic model”.

1. The cell membrane of two adjacent cells
2. Electron micrograph of two adjacent cell membrane

1. The cell membrane when seen under an electron microscope shows the tri-laminar appearance
2. Structure of a phospholipid molecule.
3. Plasma membrane

There are three types of lipids in the plasma membrane i.e., phospholipids (most abundant), glycolipids, and cholesterol.

The globular proteins of the cell membrane can float like icebergs in the sea of phospholipids therefore, this model of the cell membrane is called “fluid! mosaic model.”

Cell Membrane Further Details

Lipid Raft

In the plasma membrane, there are regions containing high concentrations of cholesterol and glycosphingolipids. These regions are called “lipid rafts.”

• Glycosphingolipids are highly saturated fatty acid chains. These along with high concentrations of cholesterol make the lipid raft area thicker than the surrounding area.
• Because of the thickness of the raft, its fluidity is less. Raft contains a large number of integral and peripheral membrane proteins, which are involved in receiving and conveying cell-specific signals.

Proteins of the Cell Membrane and their Functions

Proteins of the cell membranes are divided into two groups, that is, integral and peripheral proteins.

• The integral proteins are incorporated in the lipid bilayer, while peripheral proteins are present on the membrane surface.
• Many integral proteins pass through the entire thickness of the lipid bi-layer (Transmembrane integral proteins), while other integral proteins are embedded in the outer or inner leaflets of the liquid bilayer.

Some of these transmembrane proteins are very long and many pass through the membrane many times and are thus known as multipass proteins. The peripheral proteins are present on the membrane surface.

• Six different functional types of proteins are present in the cell membrane. These are structural, transport or carrier (pumps, channel), enzyme, receptor proteins, etc.
• Structural proteins are part of the structure of the cell membrane. These proteins are present especially where they form junctions with neighboring cells, i.e., tight junctions.
• Some proteins are? involved in the active transport of ions across the cell membrane and are called pumps. They transport the ions (Na+) and macromolecules such as amino acids and sugars from one surface of the membrane to another surface by their movement within the fluid lipid bilayer.
• Some proteins form transmembrane channels that control the entry of specific ions through the cell membrane. These channels are capable of regulating the passage of ions and molecules by closing and opening their lumen. Most channels are ion channels. There are more than 100 different types of channels.

Most common ion channels are forK+ (potassium ions) orCl (chloride ions), and fewer channels are for Na+ (sodium ions) or Ca2+ (calcium ions). Most of these channels are open all the time but the opening and closing of many more channels are guarded.

• These channels are known as “gated” channels as their opening and closing are regulated by the chemical or electrical changes occurring inside or outside the cell. When the gates are open their ions diffuse in or out of the cells.
• Proteins of cell membranes also act as receptors for specific hormones and other signaling molecules that affect the activity of cells. For example, antidiuretic hormone is the activity of cells. For example, antidiuretic hormone permeability of cell membrane. Receptor proteins are likely to be glycoproteins in nature.
• Some proteins of the membrane act as enzymes, e.g., certain ATPases are membrane-bound. The enzyme catalyzes the chemical reactions outside or inside the cell membrane.

Proteins of the Cell Membrane and their Functions Remember

Proteins of the cell membranes are divided into two I groups, that is, integral and peripheral proteins. Functionally they are divided into many types, i.e., structural, transport or carrier (pumps, channel), enzyme, and receptor proteins.

• Glycoproteins and glycolipids of cell membranes may act as cell-identity markers. With the help of this marker, a cell can recognize whether other cells are of the same kind or foreign entity, For Example., ABO blood group markers, and major histocompatibility (MHC) proteins.
• Some proteins act as linker proteins. They anchor filaments (actin) inside and (collagen) outside of the cell membrane. This helps in providing shape and stability to cells.

1. Some proteins act as channels for the transport of ions
2. Transporter proteins or pumps transport specific substances across the membrane by changing their shape
3. Receptor proteins are capable of recognizing specific ligands, which in turn may alter the cell’s function
4. Enzyme proteins can catalyze reactions occurring on the cell surface or within the cell (a ligand is a molecule that has a high affinity for receptors).

Lipid Raft Clinical Application

Defective Receptors

The defect in the receptors may lead to various kinds of diseases. A defective receptor becomes non-functioning and does not respond to its respective hormones and other signaling molecules.

For example, when growth hormone receptors are defective they do not respond to the growth hormone resulting in a type of dwarfism (abnormal short height).

Transport across the cell membrane by formation of vesicles: Endocytosis and Exocytosis

Cells are surrounded by extracellular fluid from which they derive their nutrition and release metabolites. The cell membrane permits diffusion and active transport of ions and gases into and out of the cell but prevents passive entry of most large molecules.

• The method by which large molecules or particulate matter (bacteria, red blood cells, and molecules of polysaccharides and proteins) can go in or out of the cell is called endocytosis and exocytosis respectively.
• The cell membrane takes an active part in the process of endocytosis and exocytosis. The process of endocytosis involves the formation of membrane-bound vesicles.

Endocytosis

Endocytosis is of three types, i.e., receptor-mediated endocytosis, phagocytosis, and pinocytosis.

• Receptor-mediated endocytosis is a highly selective type of endocytosis in which receptor protein in the plasma membrane recognizes and binds to specific ligands in the extracellular fluid. This receptor-ligand complex is pinched off and is taken in the form of a membrane-bound vesicle.
• The process of ingestion of solid particulate matter (e.g., bacteria, pigments, or other solid particles) is called phagocytosis. It is the process of eating by the cell.
• In the process of phagocytosis when particles come in contact with the outer surface of the cell membrane, the membrane throws pseudopodia to enclose the particles.
• When enveloping pseudopodia meet they fuse and the particles are drawn inside the cell. The invaginated membrane is then pinched off from the rest of the cell membrane and forms a phagocytic vacuole.

The process of ingestion of fluid or other small molecules is called pinocytosis. It is the process of drinking by the cell. In the process of pinocytosis when fluid molecules come in contact with the outer surface of the cell membrane, they become indented and form a pinocytic vesicle by pinching off from the rest of the cell membrane.

Exocytosis

In the process of exocytosis, there occurs the discharge of substance from the cell. The membrane-bound secretory granules of vesicles come in contact with the inner surface of the cell membrane and fuse with it. Then there is a rupture of the fused portion and the contents of the vesicle are released into the extracellular space.

Exocytosis Remember

Endocytosis is the process by which a cell ingests macro¬molecules, particulate matter, liquids, and other substances. During exocytosis, substances are discharged from the cell. Endocytosis is of three types, that is, receptor-mediated endocytosis, phagocytosis, and pinocytosis.

Exocytosis Clinical application

Receptor-mediated Endocytosis and HIV Infection

• Although receptor-mediated endocytosis is used by cells to import needed material from outside the cell, some viruses may enter the cell by this process of endocytosis.
• The human immunodeficiency virus (HIV) usually gets attached to the CD4 receptor on the plasma membrane of helper T cells (a kind of white blood cell) and enters the cell by receptor-mediated endocytosis.
• In this way, the cell gets infected with HIV which causes acquired immunodeficiency syndrome (AIDS).

Functions of Cell Membrane

• It maintains the shape (structural integrity) of the cell.
• Acts as an interface between the cytoplasm and the outside milieu (tissue fluid).
• It controls the movements of substances in and out of the cell (i.e., only selected substances are permitted to cross).
• It is capable of recognizing foreign bodies.
• It transmits the chemical signals across the membrane to elicit intracellular events. Cell signaling is the communication that occurs when signaling cells release signaling molecules that bind to the cell surface receptors of target cells.
• The cell membrane regulates the cell-to-cell interactions

Cytoplasm

In a cell, the cytoplasm extends between the plasma membrane and the nuclear envelope. The cytoplasm consists of a cytoplasmic matrix or ground substance that is also known as cytosol. The cytosol contains organelles, inclusion, and cytoskeleton.

Cytosol

The cytoplasm ground substance (cytosol) is made up of a fluid base containing ions (Na, K, Ca), various organic molecules (carbohydrates, lipids, proteins, and RNAs), and a three-dimensional network of the trabeculae.

The cytosol contains various structural elements like organelles, inclusions, and cytoskeleton.

• The organelles are the small organs of the cell. They have their distinctive structure and are involved in various biochemical processes necessary for the metabolism of the cell (For Example., endoplasmic reticulum, Golgi complex, mitochondria, lysosomes, ribosomes, and centrioles).
• The inclusions, on the other hand, are non-functioning elements of the cytoplasm. They are involved in the storage of nutrients such as glycogen and lipids, pigment, and secretory granules.
• The cytoplasm also contains a cytoskeleton that is made up of microtubules and microfilaments.

Cytosol Remember

The cytoplasm consists of the cytoplasmic matrix (cytosol), which itself contains various Structural elements like organelles, inclusions, and cytoskeleton (Microtubules and microfilaments).

Cytoplasmic Organelles

Most of the organelles are membrane-bound (this membrane is similar to the plasma membrane). Examples of membranous organelles are the endoplasmic reticulum, Golgi complex, mitochondria, lysosomes peroxisomes, and endosomes. Thus their contents and functions are confined within the membrane.

On the other hand, some organelles are not bounded by a membrane and thus come in direct contact with cytosol, For Example., ribosomes and centrosomes.

Cytoplasmic Organelles Remember

Most of the cytoplasmic organelles are bound by a membrane. This membrane is similar to the plasma membrane.

Endoplasmic Reticulum

Endoplasmic reticulum (ER) is the network of membranes that may be in the form of branching and anastomosing flattened tubules and vesicles. The lumen of these tubules and vesicles is known as a cistern.

The ER is found almost throughout the cytoplasm but predominantly present near the nucleus to which it is attached.

The ER is of two different types, i.e., rough endoplasmic reticulum (RER) and smooth (SER).

1. Secretory vesicles are transported toward the plasma membrane for exocytosis
2. Membrane vesicles that contain membrane protein
3. Some storage vesicles contain lysosomal enzymes
4. Some vesicles also originate in the Cis-face of Golgi and are retrogradely transported to RER.

Endoplasmic Reticulum RER

RER is prominent in cells that are involved in protein synthesis i.e., exocrine pancreas (secretes digestive enzymes), plasma cells (secretes antibodies), and fibroblasts which synthesize collagen.

• The RER is usually in the form of flattened sacs (cisterns) arranged one upon the other. These cisterns are connected and form a continuous system of membrane-limited cavities.
• The membrane of RER is connected with the nuclear membrane.
• On the outer surface of its membrane, numerous granules (25-30 nm in size) are attached. These granules are ribosomes that are responsible for the basophilic stain of RER.

Functions of RER

• Proteins synthesized by ribosomes enter the cavity of RER for processing and storage.
• RER is also involved in the synthesis of phospholipids.
• In the cavity of RER, the protein may combine with the carbohydrates to form glycoprotein or it may combine with phospholipids. These reactions take place under the influence of enzymes present in RER.
• Thus, RER is involved in the synthesis of secretory proteins and molecules used in the formation of plasma membranes (lipids and integral proteins).

Endoplasmic Reticulum SER

The SER also consists of short anastomosing tubules (Fig.1.9b). As the ribosomes are not attached on its surface

Functions of SER

Though SER is not involved in the synthesis of proteins, similar to RER it is also involved in the synthesis of phospholipids.

SER is involved in the synthesis of fat (cholesterol, triglycerides) and steroid hormones (estrogen, testosterone, etc.).

In the liver cells, it is involved in the detoxification of drugs and other chemicals (breakdown of alcohol and barbiturates, etc.).

SER is specialized in skeletal muscle fibers and is known as the sarcoplasmic reticulum, which helps in the control of muscle contraction.

Endoplasmic Reticulum Remember

• The endoplasmic reticulum (ER) is of two different types, i.e., rough endoplasmic reticulum (RER) and smooth endoplasmic reticulum (SER). The RER is called rough ER because of the presence of granules (ribosomes) on its surface.
• while SER is called smooth ER because ribosomes are not attached to its surface. RER is involved in the synthesis of protein, while SER in the synthesis of fat and steroid hormones.

Golgi Complex

• This cytoplasmic organelle is present in almost all cells but is well-developed in the secretory cells.
• In the glandular cells, it is present between the nucleus and the apex of the cell. It is 0.5 to 2 μm in diameter.
• It is made up of 3-20 flattened membranous sacs (cisternae) that are curved. Thus, the shape of the Golgi complex is like a shallow cup.
• The Golgi complex has a convex and a concave surface. The convex surface faces towards the RER and nucleus, while the concave surface faces towards the cell membrane.
• The convex surface is also called as forming face (cisface) and the concave surface is called the maturing face (trans-face).
• The small vesicles that bud off from the RER are transported towards the cis-face of the Golgi complex where they Rise with the outermost convex cistema of forming face.
• The secretory product then moves from the cistema of forming face to maturing face through vesicles that bud off from the periphery of one cisterna and fuse with the next.
• While the secretory products are moving from his face to fransface of Golgi, they are modified.
• At the trans-face or maturing face, the products are accumulated & concentrated in cisterna.
• Membrane-bounded secretory vesicles are formed at the trans-face that leave the Golgi and move towards the apical end of the cell for secretion.

Golgi Complex Functions

• One of the important functions of the Golgi complex is to sort proteins for their respective pathways, that is, to the plasma membrane, secretory granules, or lysosomes.
• Golgi is also involved in membrane synthesis (by forming the membrane vesicles).
• It forms secretory vesicles for exocytosis.
• It is also involved in the production of lysosomes with RER.
• Enzymes of the Golgi modify the proteins to form glycoproteins and lipoproteins. They also modify glycolipid.

Golgi Complex Remember

The Golgi apparatus is made up of a series of flattened membrane-bound cisternae. It consists of a cis-face and a trans-face. Its function is in the synthesis of carbohydrates and the modification and sorting of proteins.

Lysosomes

• Lysosomes are electron-dense, membrane-bounded bodies (vesicles), measuring 0.2-0.8 μm in diameter.
• They are formed in the Golgi complex and are called primary lysosomes. When a primary lysosome fuses with the endocytic vesicle (the contents of which are to be digested), it is called a secondary lysosome.
• Lysosomes contain 40 types of powerful hydrolytic (digestive) enzymes that are capable of breaking down various kinds of molecules.
• Lysosomal enzymes work best at acid pH. Therefore, the lysosomal matrix is 100 times more acidic than cytosol. The lysosomal membrane possesses proton pumps that actively transport H⁺ ions into the lysosome, maintaining its lumen at pH 5.
• Although lysosomes contain hydrolytic enzymes, their membrane is resistant to hydrolysis by their enzymes. This is because their membrane has an unusual phospholipid structure.

The membrane proteins in lysosomes are highly glycosylated. Sugar molecules cover the cytoplasmic surface proteins that protect them from digestion by lysosomal enzymes.

Lysosomes Functions

• Lysosomes are involved in the digestion of substances or particles (bacteria, etc), which are brought into the cell using endocytosis. This process is called heterophagy.
• Lysosomes are also capable of digesting the old (worn out) organelles of cytosol and returning the digested components to the cytosol. This process is called autophagy.
• In some pathological conditions, lysosomes may also destroy their cells. This process is known as autolysis.

Lysosomes Remember

Lysosomes have an acidic pH and contain 40 types of powerful hydrolytic (digestive) enzymes that are capable of breaking down various kinds of molecules. Lysosomes are involved in the digestion of substances or particles (bacteria, etc) that are brought into the cell using endocytosis.

Peroxisomes

• Peroxisomes are small (0.2-1 μm in diameter) ovoid organelles. This structure is almost similar to lysosomes. These are also membrane-bounded bodies containing more than 40 oxidative enzymes.
• Peroxisomes contain enzymes that oxidize amino acids and fatty acids as part of normal metabolism.
• The enzymes of peroxisomes also oxidize toxic substances like alcohol.
• In the process of oxidation, hydrogen peroxide (H₂0₂) is released as a by-product that is toxic to cells.
• Peroxisomes contain an enzyme called catalase that detoxifies H₂0₂ within the cell.

Peroxisomes Clinical Application

Tay-Sachs Disease

• This is a lysosomal storage disorder.
• This is an inherited (genetic) disease. It is due to the absence of a single lysosomal enzyme (B-hexosaminidase).
• In the absence of this enzyme, the glycolipid (ganglioside) cannot be broken down and thus accumulates in nerve cells.
• This leads to inefficient working of nerve cells resulting in seizures, muscle rigidity, blindness, and death before 5 years of age.

Mitochondria

• Mitochondria are called “powerhouses” of the cell because they generate ATP (a stable storage form of energy).
• These are present in all types of cells, except red blood cells.
• Their number within a cell may vary from a few to several thousand (about 2000 in each liver cell).
• A large number of mitochondria are present in highly active cells, e.g., muscles, liver, and kidney cells.
• This membrane-bounded organelle is elliptical in shape and measures about 0.5-3 μm in length.
• Unlike other membrane-bound organelles, mitochondria are made up of two parallel membranes each of which is structurally similar to the plasma membrane.
• The outer membrane is smooth while the inner membrane is arranged in a series of folds called cristae.

The inner membrane is rich in enzymes (ATP synthase) that are present in spherical bodies (elementary particles) attached to its inner surface. Intramembranous space contains specific enzymes.

• One of them is cytochrome C, which is important in initiating apoptosis (programmed cell death).
• The matrix is the central fluid-filled cavity of mitochondria enclosed by the inner membrane and cristae.
• Matrix contains matrix granules, mitochondrial DNA filaments, mRNA, tRNA, and rRNA.
• Mitochondrial DNA consists of a double helix in the form of a circle that contains 37 genes.
• It is believed that mitochondrial genes are inherited only from the mother as the head of sperm lacks mitochondria.
• As per the energy requirement of the cell, mitochondria may divide to increase their number. Mitochondria are present in all cells, except those lacking nuclei, i.e., RJBCs and terminal keratinocytes.
• It shows an electron micrograph of mitochondria.

The average life span of mitochondria is about 10 days. They are self-replicating. The mitochondrion enlarges in size, replicates its DNA, and undergoes division to form two mitochondria.

Mitochondria Functions

• As the matrix of mitochondria also contains ribosomes, some protein synthesis occurs within the mitochondria, Mitochondria are capable of synthesizing their ribosomal protein.
• The remainder of the mitochondrial proteins is encoded by the nuclear DNA, which then comes from cytoplasm to mitochondria.
• Mitochondria are involved in the production of a high-energy phosphate compound, adenosine triphosphate (ATP).
• This ATP is a stable storage form of energy, which is used for many chemical reactions in the cell.
• Granules of the matrix arc cation-binding sites. Thus, the mitochondria arc is also involved in the regulation of the concentration of certain ions in the cytosol.
• Mitochondria sense cellular stress and decide whether the cell should live or die by initiating apoptosis (programmed cell death).

Mitochondria Remember

Mitochondria are present in all cells except those lacking nuclei, i.e., RBCs and terminal keratinocytes, A Large number of mitochondria is present in highly active cells, For Example., muscles, liver, and kidney cells. As per the energy requirement of the ceil, mitochondria may divide to increase their number. Mitochondria are involved in the Production of a high-energy phosphate compound, ATP.

Ribosomes

• Ribosomes are small particles about 20 to 30 nm in diameter. They contain ribonucleic acid and many types of ribosomal proteins.
• Ribosomes are made up of two subunits both of which are produced separately in nucleolus. Once produced they migrate to the cytosol and both subunits join each other.
• Ribosomes are attached in groups on the surface of RHR. This group of ribosomes is called polyribosomes. They are present in groups because they are attached to the thread of messenger RNA.
• Ribosomes are also scattered singly or in groups in cytoplasm (not attached to any organelle). These types of ribosomes are called free ribosomes or free polyribosomes, respectively.

Ribosomes Functions

• Ribosomes are the site of protein synthesis.
• Free ribosomes synthesize proteins that are used within the cell.
• Membrane-bound ribosomes are involved in the synthesis of secretory proteins. They also synthesize proteins used in the formation of new plasma membranes.

Centrosome or Microtubule Organizing Centre

• The centrosome is a small spherical area of cytoplasm situated near the nucleus.
• It consists of two parts: the pericentriolar area and the centriole.
• The pericentriolar area is made up of a dense network of smaller granular protein material.
• In the center of the pericentriolar area, two rod-shaped structures are called centrioles. The long axis of one centriole is at a right angle to the long axis of the other.
• Centrioles are hollow cylindrical structures each of which is made up of nine groups of three microtubules (triplets) arranged in a circular pattern.
• Centrioles are self-replicating organelles. Just before cell division, a new centriole is synthesized near the old one.

Centrosome or Microtubule Organizing Centre Functions

• The pericentriolar area plays an important role in the formation of mitotic spindles during cell division.
• In a non-dividing cell, this is also involved in the synthesis of microtubules.
• Centrioles are involved in the formation of cilia and flagella.

1. The pericentriolar area of a centrosome surrounds two centrioles. The long axes of two centrioles are perpendicular to one another.
2. Transverse section across a centriole. Each centriole is made up of 9 bundles of microtubules, with 3 microtubules per bundle.
3. Electron microscopic image of the centrosome, in which two centrioles (in longitudinal section) are seen arranged at a right angle to each other.
4. Electron micrograph of a centriole as seen in the transverse section. Three microtubules are visible in each 9 bundles.

Endosomes

• Endosomes are membrane-bounded compartments (between 100 to 500 nm in size) associated with endocytotic pathways. There are two types of endosomes, i.e., early and late endosomes.
• Early endosomes are located near the cell membrane. The endocytotic vesicles, which originate from the cell membrane, fuse with the early endosomes.
• The function of early endosomes is to sort the proteins received through endocytotic vesicles. Receptor proteins will go back to the plasma membrane.
• While the remaining proteins will be transported to the late endosomes through multivesicular bodies. The multivesicular bodies are structures that transport proteins between early and late endosomes.
• Late endosomes are located near the Golgi apparatus. The substances transported to late endosomes are degraded in the lysosomes.

Cytoplasmic Inclusions

Inclusions are non-living and non-functional components of a cell. They are simply the store of inert by-products of metabolism like lipids and glycogen. These are not membrane-bound.

• Glycogen: Glycogen is present in the cytoplasm in the form of dense granules that are about 25-30 nm in diameter.
• Lipid: Lipid is stored in the cytoplasm in the form of rounded droplets.
• Pigments: Some cells may show the presence of a yellowish-brown pigment called lipofuscin. These inclusions may be membrane-bound. The lipofuscin pigments are waste products of the cell, which cannot be digested completely by the lysosomal activity.
• Secretory granules: Sometimes, the membrane-bounded secretory vesicles are also classified as cytoplasmic inclusions.

Cytoskeleton

Different kinds of protein filaments and tubules form a network throughout the cytoplasm. This network is called a cytoskeleton. The cytoskeleton provides shape to the cell and organizes the cellular contents.

Cytoskeleton is also involved in the mobility of some cells, For Example., phagocytes. The cytoskeleton consists of the following three types of protein filaments:

• Microfilaments
• Intermediate filaments
• Microtubules

1. Microfilament

• Microfilaments are the thinnest (5 nm in diameter) filaments of the cytoskeleton. These filaments are mainly present near the peripheral part of the cell and are made up of proteins called actin.
• Microfilaments provide shape to the cell. They also provide the skeleton of microvilli, which are finger-like projections from the cell surface.
• Microfilaments are also involved in muscle contraction, cell division, and movement of phagocytes and other cells.

2. Intermediate Filaments

• The intermediate filaments are thicker (10 nm in diameter) than microfilaments. These filaments are found in parts of cells subjected to mechanical stress.
• The intermediate filaments of nerve cells are called neurofilaments. The tonofibrils are filaments of epidermal cells that are composed of a protein called keratin.

Cytoskeleton Clinical Application

Alzheimer’s Disease

• Failure to assemble the intermediate filaments leads to various diseases. The changes in neurofilaments lead to Alzheimer’s disease.
• In this disease, there is an accumulation of tangled masses of filaments in the cytoplasm leading to the degeneration of neurons. Patients with this disease suffer from loss of memory.

Microtubules

Microtubules are hollow cylinders about 25 nm in diameter and several microns in length. They are made up of the protein tubulin. Microtubules are assembled at the centrosome, which consists of a microtubule-organizing center.

• Microtubules are present throughout the cytoplasm where they are involved in giving shape to cells, in the intracellular transport of secretory granules, and movements of chromosomes during cell division.
• These tubules are also present in cilia and flagella and are responsible for their movements.

Nucleus

The nucleus is a membrane-bound structure. It is either a spherical or oval-shaped structure, present usually in the center of the cell.

It contains genes, which control cellular structure and the various activities of the cell. The nucleus consists of an envelope (nuclear envelope), nuclear lamina, chromatin material, nucleolus, and nuclear matrix.

Nuclear Envelope

The nuclear envelope is made up of two parallel membranes that separate the nucleus from the cytoplasm. These membranes are similar to plasma membranes.

• The outer nuclear membrane is continuous with rough endoplasmic reticulum.
• In the nuclear membrane, there are several channels, which are called nuclear pores. Small molecules and ions diffuse passively through these pores.
• However, the transport of large protein molecules from the cytosol to the nucleus and that of RNAs from the nucleus to the cytosol is regulated by nuclear pores.

Nuclear Lamina

The nuclearlamina is a thin layer adjacent to the inner nuclear membrane. It is formed by intermediate filaments, which are arranged in a square lattice.

• The function of nuclear lamina is to provide structural stability to the interphase nucleus (nuclear envelope, nuclear pores, and chromatin).
• The nuclear lamina disintegrates during cell division but reassembles in the daughter cells.

Chromatin

The nucleus plays an important role in heredity. It contains heredity units called genes. Genes are present on chromosomes, which itself is a long molecule of DNA coiled together with several proteins.

• Innon-dividing cell (interphase cell), chromosomal material is less tightly coiled and appears as a diffuse granular mass, which is called chromatin.
• The chromatin is stained basophilic (with hematoxylin) due to the presence of a phosphate group in DNA. In the nucleus of an interphase cell, chromatin occurs in two different arrangements, i.e., heterochromatin (condensed chromatin) and euchromatin (extended chromatin).
• Heterochromatin stains with basic dyes and hematoxylin and thus appears as irregular dark masses. Euchromatin stains lightly with basic dyes and is seen as clear areas between heterochromatin.
• Nuclei that are predominantly made up of euchromatin are called open-face nuclei, while nuclei that are made up mainly of heterochromatin are called closed-face nuclei.

Heterochromatin is regarded as metabolically inactive chromatin (For Example, chromatin in the head of sperm), while euchromatin is active chromatin (chromatin of neurons and liver cells).

Nucleolus

The nucleolus is the spherical body within the nucleus that is stained dark with basic dyes. Some cells contain more than one nucleolus.

• It contains a protein called nucleostemin. It is a P53 binding protein that regulates the cell cycle and influences cell differentiation.
• The main role of the nucleolus is to synthesize rRNA and assemble ribosomes.
• When observed under an electron microscope, it consists of three regions.
• The innermost pale staining fibrillar center (FC) is surrounded by a dense fibrillar component (DFC) or pars fibrosis, which in turn is bounded by a granular component (GC) or pars granulosa. Pars granulosa contains maturing ribosomes.
• Transcription of DNA occurs in FC or at the FC-DFC junction. This region contains tips of chromosomes 13, 14, 15, 21, and 22 (the nucleolar organizing regions), where gene loci that encode rRNA are located.
• Most of the cleavage and modification of RNA occurs in the DFC. While steps involving protein assembly to form preribosomal particles occur in GC.

Here, small and large ribosomal subunits are organized, which migrate to the cytoplasm through nuclear pores.

Nuclear Matrix

All the material enclosed by the nuclear membrane, excluding chromatin and nucleolus, is called nucleoplasm. At present, nothing much is known about its composition but it seems that it must contain a network of fibrils (karyoskeleton), proteins, and metabolites.