5)Gastrointestinal Physiology 2(1)_3.pdf

Gastrontestinal Physiology 2 Prof.Dr. Haluk KELEŞTİMUR Istanbul Okan University Medical School Department of Physiology Salivary Secretion Major Secretions into the GI Tract Regulation of Gastrointestinal Secretions Major Salivary Glands The epithelial cells of the salivary glands are arranged in se...

Gastrontestinal Physiology 2 Prof.Dr. Haluk KELEŞTİMUR Istanbul Okan University Medical School Department of Physiology Salivary Secretion Major Secretions into the GI Tract Regulation of Gastrointestinal Secretions Major Salivary Glands The epithelial cells of the salivary glands are arranged in secretory endpiece (acinus) connected to the oral mucosa by a system of ducts The acinus and canal system of the salivary glands The general features of the salivary glands The composition of salivary secretion in the different flow rate (a) and representation of the two-stage model of salivary secretion (b) Saliva is hypotonic to plasma at all flow rates. [HCO3-] in saliva exceeds that in plasma except at very low flow rates. The primary secretion is produced in the acinar cell. The concentration of electrolytes in plasma is similar to that in the primary secretion, but is modified as it passes through ducts that absorb Na+ and Cl- and secrete K+ and HCO3-. The duct cells are not permeable to H2O. The reflex control of salivary secretion Regulation of salivary secretion by the autonomic nervous system Control of salivary secretion by nerves Model for acinar ion transport mechanisms involved in salivary fluid formation (cont’d) A. B. C. Fluid secretion is an active process, dependent upon the active transport of electrolytes by the secretory cells. The parasympathetic innervation provides the main stimulus for fluid and electrolyte secretion. Acetylcholine shows its effect via binding to G-protein coupled muscarinic receptors with IP3-Ca2+ second messenger pathway. The increase in cytoplasmic Ca2+ opens Cl- channels in the luminal membrane and K+ channels in the basolateral membrane of the secretory cells. Intracellular Cl- enters the lumen, drawing extracellular Na+ ions through the tight junctions to balance the electrochemical gradient. The resulting osmotic gradient pulls water into the lumen, both through the tight junctions and via water channels (aquaporins) in the secretory cell membranes. The secretion of proteins and glycoproteins occurs by the process of exocytosis. Binding of norepinephrine released from sympathetic nerve terminals to G-protein coupled β-adrenergic receptors activates cAMP second messenger, leading to exocytosis in serous cells. During active fluid secretion, intracellular ionic and osmotic balance is maintained by Na+/K+/2Cl- cotransporters, Na+/H+ exchangers, and Na+/K+-ATPase in the basolateral membrane. With strong stimulation that results in high salivary flow rates, HCO3- , which may be formed intracellularly by carbonic anhydrase, enter the lumen via the Cl− channels. The transient intracellular acidification caused by the efflux of HCO3- is recovered by up-regulated activity of the basolateral Na+/H+ exchanger, which can use the Na+ gradient established by the Na+/K+ ATPase to export protons. Sources of salivary biomarkers Salivary fluid is primarily derived from salivary gland secretion. Most of the protein content of saliva comes from the salivary proteins that are synthesized and secreted by salivary acinar cells. Saliva in the mouth also contains epithelial cells shed from the mucosal surfaces, blood cells (neutrophils) from gingivae and oral microorganisms made up of a rich mix of bacterial species and candida. Small amounts of blood and tissue fluid proteins enter saliva mainly from the gingivae as gingival crevicular fluid (GCF) content. The composition of whole saliva The Features of Salive The amount produced at any given time depends on several factors, including autonomic nervous system activity, body hydration, the time of day, and drug use. Secretion from the major glands also follows a circadian pattern, with the greatest (unstimulated) output between noon and 6 p.m., and the least output between midnight and 6 a.m. Although producing only a small volume, the minor glands secrete almost continuously, and therefore have an important role in moistening, lubricating, and protecting the oral mucosa and teeth during sleep. A side effect of many commonly prescribed medications is dry mouth, caused by central or peripheral inhibition of saliva secretion. The flow rate of unstimulated whole saliva varies between 0.2 and 0.5 mL/minute. With maximal stimulation, the whole saliva flow rate can exceed 7 mL/minute. The volume of saliva in the mouth at any given time varies between about 0.6 and 1.2 mL, following and just prior to swallowing. This volume is spread over the entire oral cavity, creating a salivary film 0.07 to 0.1 mm thick coating the mucosa and teeth. The functions of saliva The Protective Functions of Saliva Clearance: The dilution and clearance of food debris, microbial acids, and other products is facilitated by the constant flow of the salivary film across the teeth and mucosa, which moves at different rates with 0.8 mm per minute along the facial surfaces of the maxillary incisors, whereas under stimulated conditions 300 mm per minute along the lingual surfaces of the mandibular incisors. Lubrication: The negatively charged mucins and glycoproteins, with abundant bound water, help to lubricate the mucosa and teeth and allow tissues to slide past one another during chewing, swallowing, and speaking. Thermal/Chemical Insulation: A coating of mucins on the oral surfaces helps to protect against thermal, chemical, and mechanical insults. Pellicle: Many salivary constituents, including mucins, acidic proline-rich proteins (PRPs), statherin, histatins, and cystatins, bind to the enamel surface, forming a salivary pellicle. These bound constituents create a reservoir of calcium and phosphate at the tooth surface that opposes demineralization and promotes remineralization of initial caries lesions, especially in the presence of F− ions. Toxin Binding: The basic PRPs and histatins bind tannins (common constituents of many plant-derived foods that may inhibit growth and have various toxic effects) and prevent their uptake by intestinal epithelial cells. Buffering Salivary HCO3− and carbonic anhydrase play important roles in counteracting the effects of microbial acids generated from sugars on the hydroxyapatite crystals of enamel and dentin. Salivary HCO3− levels increase as salivary flow increases, and in the presence of H+, carbonic anhydrase in saliva or bound to teeth in the salivary pellicle forms H2O and CO2, and the CO2 escapes into the air. Some buffering also is achieved by HPO42− and H2PO4− in saliva, as well as by cationic, histidine-rich proteins. Additionally, urea and ammonia formed by microbial metabolism help to neutralize acids. Antimicrobial Activity Saliva contains a number of proteins that function in regulating the oral microbial flora. Some of the proteins, such as lysozyme and peroxidase, are enzymes that attack microbial cell walls or generate products that inhibit microbial metabolism. Other proteins, such as mucins, salivary agglutinin (gp340), and the major salivary immunoglobulin, secretory immunoglobulin A (sIgA), bind to and aggregate microorganisms, preventing them from binding to oral tissues. SPLUNC (short palate lung nasal epithelium clone) family proteins, in addition to binding and inhibiting growth of certain bacteria, bind lipopolysaccharide (LPS) and prevent release of inflammatory mediators from macrophages. Some small peptides, such as defensins, cathelicidin LL-37, and the histatins, insert into and disrupt microbial cellular membranes, resulting in osmotic lysis or depletion of various metabolites. Lactoferrin binds iron, reducing its availability to microorganisms, and also disrupts cellular membranes. Secretory leukocyte protease inhibitor (SLPI) binds to and inhibits certain bacteria and exhibits anti-viral activity. Tissue Repair Growth factors present in saliva, such as epidermal growth factor, and other salivary proteins (e.g., trefoil factor family peptides, histatins) are believed to facilitate wound healing and tissue repair. These factors may induce cell proliferation and migration during wound healing and re-epithelialization in the oral cavity and the digestive tract. Trefoil proteins are thought to promote healing of ulcers in the oral cavity and digestive tract; they are produced by salivary mucous cells and also by keratinocytes of the oral epithelium. Digestion Saliva has an important role in eating and digestion. Saliva serves to facilitate mastication and swallowing of food and solubilizes many food constituents. During mastication, the water and mucins in saliva protect the oral tissues and help to create a food bolus suitable for swallowing. Saliva also contains several enzymes that initiate digestion of various dietary constituents. These include amylase, which hydrolyzes starches to maltose and limit dextrins, ribonuclease (RNAse) and deoxyribonuclease (DNAse). Lingual lipase, produced by the lingual serous glands and pharyngeal glands, initiates digestion of dietary triglycerides. Although digestion of these substances is achieved mainly by pancreatic and gastric enzymes, the salivary enzymes may play a significant role in cases of pancreatic insufficiency. Taste The solubilization of food makes possible the detection of taste substances by taste receptors in taste buds of the tongue. Clearance of taste substances by saliva permits detection of new taste stimuli. The salivary salt (NaCl) concentration is only one seventh of that in the plasma, which is important in perceiving salty taste.The taste receptors are adapted to the concentration of Na+ in saliva; the threshold for the salty taste of NaCl is greater and the supra-threshold intensity is less in the presence of saliva than distilled water. The absence of glucose in saliva at all is important in the formation of the feeling of sweetness. Some components of saliva may interact with taste substances and modify their effect. For example, HCO3− in saliva reacts with acid (H+), reducing its taste intensity. Basic PRPs bind to tannins, diminishing or altering their bitter taste or interfering with taste reception. Gastric Secretion Structure of a gastric oxyntic gland showing the various cell types lining the gland Secretory products of various gastric cells Functional anatomy of the stomach Mechanism of HCl secretion by gastric parietal cells 1. In intracellular fluid, carbon dioxide (CO2) produced from aerobic metabolism combines with H2O to form H2CO3, catalyzed by carbonic anhydrase. H2CO3 dissociates into H+ and HCO3−. The H+ is secreted with Cl− into the lumen of the stomach, and the HCO3 − is absorbed into the blood, as described in Steps 2 and 3, respectively. 2. At the apical membrane, H+ is secreted into the lumen of the stomach via the H+-K+ ATPase. The H+-K+ ATPase is a primary active process that transports H+ and K+ against their electrochemical gradients (uphill). H+-K+ ATPase is inhibited by the drug omeprazole, which is used in the treatment of ulcers to reduce H+ secretion. Cl− follows H+ into the lumen by diffusing through Cl− channels in the apical membrane. Mechanism of HCl secretion by gastric parietal cells 3. At the basolateral membrane, HCO3− is absorbed from the cell into the blood via a Cl− -HCO3− exchanger. The absorbed HCO3 − is responsible for the “alkaline tide” (high pH) that can be observed in gastric venous blood after a meal. Eventually this HCO3− will be secreted back into the gastrointestinal tract in pancreatic secretions. 4. In combination, the events occurring at the apical and basolateral membranes of gastric parietal cells result in net secretion of HCl and net absorption of HCO3−. Functions of HCl HCl activates the enzyme precursor pepsinogen to an active enzyme, pepsin, and provides an acid environment optimal for pepsin action. It aids in the breakdown of connective tissue and muscle fibers, reducing large food particles into smaller particles. It denatures protein—that is, it uncoils proteins from their highly folded final form, thus exposing more of the peptide bonds for enzymatic attack. Along with salivary lysozyme, HCl kills most of the microorganisms ingested with food, although some escape and then grow and multiply in the large intestine. Agents that stimulate and inhibit H+ secretion by gastric parietal cells Stimulation of gastric secretion Inhibition of gastric secretion Gastric mucosal barrier 1. 2. 3. 4. The luminal membranes of the gastric mucosal cells are impermeable to H+ so that HCI cannot penetrate into the cells. The cells are joined by tight junctions that prevent HCI from penetrating between them. A mucus coating over the gastric mucosa serves as a physical barrier to acid penetration. The HCO3 – -rich mucus also serves as a chemical barrier that neutralizes acid in the vicinity of the mucosa. Even when luminal pH is 2, the mucus pH is 7. Pepsinogen secretion Pepsinogen, the inactive precursor to pepsin, is secreted by chief cells and by mucous cells in the oxyntic glands. When the pH of gastric contents is lowered by H+ secretion from parietal cells, pepsinogen is converted to pepsin, beginning the process of protein digestion. Once formed, pepsin acts on other pepsinogen molecules to produce more pepsin, a mechanism called an autocatalytic process. In the cephalic and gastric phases of H+ secretion, vagal stimulation is the most important stimulus for pepsinogen secretion. H+ also triggers local reflexes, which stimulate the chief cells to secrete pepsinogen. Intrinsic Factor Secretion Intrinsic factor, a mucoprotein, is the “other” secretory product of the parietal cells. Intrinsic factor is required for absorption of vitamin B12 in the ileum, and its absence causes pernicious anemia. Intrinsic factor is the only essential secretion of the stomach. Thus following gastrectomy (removal of the stomach), patients must receive injections of vitamin B12 to bypass the absorption defect caused by the loss of gastric intrinsic factor. Pancreatic secretion The pancreas is a mixture of exocrine and endocrine tissue. The smaller endocrine part consists of isolated islands of endocrine tissue, the islets of Langerhans, which are dispersed throughout the pancreas. The most important hormones secreted by the islet cells are insulin and glucagon. The exocrine pancreas secretes digestive enzymes and an alkaline fluid. (1) pancreatic enzymes actively secreted by the acinar cells that form the acini and (2) an aqueous alkaline solution actively secreted by the duct cells that line the pancreatic ducts. The aqueous (watery) alkaline component is rich in sodium bicarbonate (NaHCO3). Composition of pancreatic juice The activation of pancreatic juice enzymes When trypsinogen is secreted into the duodenal lumen, it is activated to its active enzyme form, trypsin, by enteropeptidase (formerly known as enterokinase), an enzyme embedded in the luminal membrane of the cells that line the duodenal mucosa. Trypsin then autocatalytically activates more trypsinogen. Like pepsinogen, trypsinogen must remain inactive within the pancreas to prevent this proteolytic enzyme from digesting the proteins of the cells in which it is formed. As further protection, the pancreas also produces a chemical known as trypsin inhibitor, which blocks trypsin’s actions if spontaneous activation of trypsinogen inadvertently occurs within the pancreas. Chymotrypsinogen and procarboxypeptidase are converted by trypsin to their active forms, chymotrypsin and carboxypeptidase, respectively, within the duodenal lumen. Thus, once enteropeptidase has activated some of the trypsin, trypsin carries out the rest of the activation process Mechanism of pancreatic secretion Hormonal control of pancreatic exocrine secretion The factors regulating pancreas secretion following a meal The liver and bile secretion 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Secretion of bile salts, which aid fat digestion and absorption. This is the only liver function directly related to digestion. The first role of bile salts is to emulsify dietary lipids. Without emulsification, dietary lipids would coalesce into large “blobs,” with relatively little surface area for digestion. The second role of bile salts is to form micelles with the products of lipid digestion including monoglycerides, lysolecithin, and fatty acids. Metabolic processing of the major categories of nutrients (carbohydrates, proteins, and lipids) after their absorption from the digestive tract. Detoxifying or degrading body wastes and hormones, as well as drugs and other foreign compounds Synthesizing plasma proteins, including those needed for blood clotting, those that transport steroid and thyroid hormones and cholesterol in the blood, and angiotensinogen important in the salt conserving renin–angiotensin–aldosterone system Storing glycogen, fats, iron, copper, and many vitamins Activating vitamin D, which the liver does in conjunction with the kidneys Secreting the hormones thrombopoietin (stimulates platelet production), hepcidin (inhibits iron uptake from the intestine), and insulin-like growth factor-I (stimulates growth) Producing acute phase proteins important in inflammation Excreting cholesterol and bilirubin, the latter being a breakdown product derived from the destruction of worn-out red blood cells Removing bacteria and worn-out red blood cells Enterohepatic circulation of bile salts 1. Bile contains several organic constituents, namely, bile salts, cholesterol, lecithin, and bilirubin. Even though bile does not contain any digestive enzymes, it is important for the digestion and absorption of fats, primarily through the activity of bile salts. 2. Bile salts are derivatives of cholesterol. They are actively secreted into the bile and eventually enter the duodenum, along with the other biliary constituents. Following their participation in fat digestion and absorption, most bile salts are reabsorbed into the blood by special active-transport mechanisms located only in the terminal ileum. From here, bile salts are returned by the hepatic portal system to the liver, which resecretes them into the bile. This recycling of bile salts (and some of the other biliary constituents) between the small intestine and the liver is called the enterohepatic circulation. 3. The total amount of bile salts in the body averages about 3 to 4 g, yet 3 to 15 g of bile salts may be emptied into the duodenum in a single meal. On average, bile salts cycle between the liver and the small intestine twice during the digestion of a typical meal. Usually, only about 5% of the secreted bile escapes into the feces daily. These lost bile salts are replaced by new bile salts synthesized by the liver; thus, the size of the pool of bile salts is kept constant. DIGESTION AND ABSORPTION Digestive Processes for the Three Major Categories of Nutrients Carbohydrate digestion Carbohydrate absorption Protein digestion Protein absorption 1. 2. 3. 4. Dietary fat in the form of large fat globules composed of triglycerides is emulsified by the detergent action of bile salts into a suspension of smaller fat droplets. Lipase hydrolyzes the triglycerides into monoglycerides and free fatty acids. These water-insoluble products are carried to the luminal surface of the smallintestine epithelial cells within water-soluble micelles, which are formed by bile salts and other bile constituents. When a micelle approaches the absorptive epithelial surface, the monoglycerides and fatty acids leave the micelle and passively diffuse through the lipid bilayer of the luminal membranes. 5. The monoglycerides and free fatty acids are resynthesized into triglycerides inside the epithelial cells. 6. These triglycerides aggregate and are coated with a layer of lipoprotein from the endoplasmic reticulum to form water-soluble chylomicrons. 7. Chylomicrons are extruded through the basal membrane of the cells by exocytosis. 8. Chylomicrons enter the lymphatic vessels, the central lacteals.