1、Gastrointestinal Physiology (Part 2),Xia Qiang, MD & PhDDepartment of PhysiologyZhejiang University School of MedicineEmail: ,Pancreatic secretion,Pancreatic juice,pH 7.88.41500 ml/dayIsosmotic Components:Pancreatic digestive enzymes: secreted by pancreatic aciniSodium bicarbonate: secreted by small
2、 ductules and larger ducts,At low magnification,At higher magnification,Secreted by the epithelial cells of the ductules and ducts that lead from aciniUp to 145mmol/L in pancreatic juice (5 times that in the plasma)Neutralizing acid entering the duodenum from the stomach,Secretion of bicarbonate ion
3、s,Pancreatic acinar cell secretory products,Carbohydrates - Pancreatic amylase Pancreatic lipaseFat Cholesterol esterase Phospholipase TrypsinogenProteins Chymotrypsinogen Procarboxypolypeptidase Proelastase,Secretion of pancreatic digestive enzymes,Starches,Maltose and 3 to 9 glucose polymers,Pancr
4、eatic amylase,Trypsin InhibitorInhibits the activity of trypsin and thus guards against the possible activation of trypsin and the subsequent autodigestion of the pancreas,Regulation of pancreatic secretion,Basic stimuli that cause pancreatic secretionAchCholecystokinin:Secreted by I cellsStimulates
5、 the acinar cells to secrete large amounts of enzymesSecretin: Released by S cellsActs primarily on the duct cells to stimulate the secretion of a large volume of solution with a high HCO3- concentration,Stimulation of protein secretion from the pancreatic acinar cell. A, The pancreatic acinar cell
6、has at least two pathways for stimulating the insertion of zymogen granules and thus releasing digestive enzymes. ACh and CCK both activate G , which stimulates PLC, which ultimately leads to the activation of PKC and the release of Ca . Elevated Ca also activates calmodulin (CaM), which can activat
7、e protein kinases (PK) and phosphatases (PP). Finally, VIP and secretin both activate G , which stimulates adenylyl cyclase (AC), leading to the production of cAMP and the activation of PKA. B, Applying a physiological dose of CCK (i.e., 10 pM) triggers a series of Ca oscillations, as measured by a
8、fluorescent dye. However, applying a supraphysiological concentration of CCK (1 nM) elicits a single large Ca spike and halts the oscillations. Recall that high levels of CCK also are less effective in causing amylase secretion.,In addition to protein, acinar cells in the pancreas secrete an isotoni
9、c, plasma-like fluid.Stimulation of isotonic NaCl secretion by the pancreatic acinar cell. Both ACh and CCK stimulate NaCl secretion, probably through phosphorylation of basolateral and apical ion channels.The rise in Cl produced by basolateral Cl uptake drives the secretion of Cl down its electroch
10、emical gradient through channels in the apical membrane. As the transepithelial voltage becomes more lumen negative, Na moves through the cation-selective paracellular pathway (i.e., tight junctions) to join the Cl secreted into the lumen. Water also moves through this paracellular pathway, as well
11、as through aquaporin water channels on the apical and basolateral membranes. Therefore, the net effect of these acinar cell transport processes is the production of an isotonic, NaCl-rich fluid that accounts for 25% of total pancreatic fluid secretion.,Regulation of pancreatic secretion,Phases of pa
12、ncreatic secretion: A meal triggers cephalic, gastric, and intestinal phases of pancreatic secretionCephalic PhaseGastric PhaseIntestinal Phase,The three phases of pancreatic secretion,Three phases of pancreatic secretion. A, During the cephalic phase, the sight, taste, or smell of food stimulates p
13、ancreatic acinar cells, through the vagus nerve and muscarinic cholinergic receptors, to release digestive enzymes and, to a lesser extent, stimulates duct cells to secrete HCO and fluid. The release of gastrin from G cells is not important during this phase. During the gastric phase, the presence o
14、f food in the stomach stimulates pancreatic secretionsprimarily from the acinar cellsthrough two routes. First, distention of the stomach activates a vagovagal reflex. Second, protein digestion products (peptones) stimulate G cells in the antrum of the stomach to release gastrin, which is a poor ago
15、nist of the CCK receptors on acinar cells. B, The arrival of gastric acid in the duodenum stimulates S cells to release secretin, which stimulates duct cells to secrete HCO and fluid. Protein and lipid breakdown products have two effects. First, they stimulate I cells to release CCK, which causes ac
16、inar cells to release digestive enzymes. Second, they stimulate afferent pathways that initiate a vagovagal reflex that primarily stimulates the acinar cells through M cholinergic receptors.,Mechanisms that protect the acinar cell from autodigestion,Acute pancreatitis,Acute pancreatitis,Acute pancre
17、atitis is sudden swelling and inflammation of the pancreasThe symptomatology and complications of acute pancreatitis are caused by autodigestion (resulting from the leakage of pancreatic enzymes) of the pancreas and surrounding tissueIt is commonly due to biliary tract disease, complications of heav
18、y alcohol use, or idiopathic causesMortality rates range from below 10% to more than 50%, depending on severity,Bile secretion,Bile is stored and concentrated in the gall bladder during the interdigestive period,Synthesis of bile acids,Composition of bile,HCO3- Bile saltsPhospholipids Cholesterol Bi
19、le pigments (include: bilirubin),Excretion of bilirubin,Jaundice,Jaundice is the most visible manifestation of an underlying hepatic and/or biliary tract disease. This is a yellow discoloration of the skin, sclerae, and mucous membranes that occurs secondary to elevated serum bilirubin in adults. Ja
20、undice is usually not clinically apparent until the serum bilirubin concentration is 2.5mg/dL.,Functions of bile,Emulsifying or detergent function of bile saltsBile salts help in the absorption of:Fatty acidMonoglyceridesCholesterol Other lipids,Emulsifying large fat particles to facilitate its dige
21、stion,Bile salts interact with cholesterol to form micelles to facilitate the absorption of insoluble fat products,Increasing bile synthesis & secretion,Enterohepatic circulation of bile acids,Regulation of bile secretion,Substances increasing bile productionBile salts (Enterohepatic circulation of
22、the bile) Secretin: stimulating H2O and HCO3- secretion from the duct cellsSubstance inhibiting bile productionSomatostatin,Contraction of the gall bladder Substances causing gall bladder contraction AChCCK Gastrin,Secretin and cholecystokinin are produced and secreted by cells in the lining of the
23、alimentary tract. Which of the following statements about these 2 secretions is true? A They are produced by enteroendocrine cells in the lining of the stomach B They are digestive enzymes present within the lumen of the duodenum C They are produced by Paneth cells D They are hormones whose target c
24、ells are primarily in the pancreas and biliary tract E They are produced by Brunners glands and released into the lumina of the crypts of Lieberkhn,Liver bile flow is increased by: A Gastrin. B Pancreatic secretion. C Vagal stimulation. D Sympathetic nerve stimulation,Small intestine,Small intestina
25、l juices,Secreted by:Brunners glandsCrypts of Lieberkuhn13 L/daypH 7.6IsosmoticComponentsH2OElectrolytes (Na+, K+, Ca2+, Cl-)MucusIgAEnterokinase,Small intestinal juices,Function: Completing the digestion of peptides, carbohydrates & fat Secretion by intestinal glands is mainly due to the local effe
26、cts of chyme in the intestine and is regulated by both neural and hormonal factors,Movement of small intestine during digestion,Tonic contraction: maintaining a basal state of intestinal smooth muscle contractionSegmentation: consisting of the alternate contraction and relaxation of adjacent bands o
27、f circular smooth musclePeristalsis: a ring of muscle contraction appears on the oral side of a bolus of ingesta and moves toward the anus, propelling the contents of the lumen in that direction; as the ring moves, the muscle on the other side of the distended area relaxes, facilitating smooth passa
28、ge of the bolus,Migrating motor complex (MMC),Local areas of peristaltic contractionPresent in the interdigestive period and disappear when feeding beginsSweeping material (undigested food residues, dead mucosal cells, bacteria) into the colon and keeping the small intestine cleanRegulated by autono
29、mic nerves and by the release of motilin,Contractions at three loci in the small bowel. Note that at each locus, phases of no or intermittent contractions are followed by a phase of continuous contractions that ends abruptly. Also note that the phase of continuous contractions appears to migrate abo
30、rally along the bowel. Such a pattern is called the migrating motor complex (MMC). min, minute; mm Hg, millimeters of mercury,Regulation of intestinal motility,Autoregulation: Regulated by BERNeural Reflexes: mainly by short reflexes in the intrinsic plexuses which are responsible for peristalsis an
31、d segmentationalso by extrinsic nerves (sympathetic & vagal nerves) which mediate long reflexesHormonal control: Gastrin, CCK, motilin, 5-HT (+)Secretin, VIP, glucagon (-),Large intestine,Function of large intestine,The principle functions of the colon:Absorption of water and electrolytes from the c
32、hyme to form solid fecesStorage of fecal matter until it can be expelledDigestion in large intestine: very limitedBacteria: vitamin B, K,Motility of the colon,Haustration: mixing movementMass movement: propulsive movementSegmentation,A normal colon, with the typical haustration,Two mass movements. A
33、, Appearance of the colon before the entry of barium sulfate. B, As the barium enters from the ileum, it is acted on by haustral contractions. C, As more barium enters, a portion is swept into and through an area of the colon that has lost its haustral markings. D, The barium is acted on by the retu
34、rning haustral contractions. E, A second mass movement propels the barium into and through areas of the transverse and descending colon. F, Haustrations again return. This type of contraction accomplishes most of the movement of feces through the colon,Absorption,General mechanisms of digestion and
35、absorption,Sites of nutrient absorption,Major gastrointestinal diseases and nutritional deficiencies,Carbohydrates,The three monosaccharide products of carbohydrate digestion glucose, galactose, and fructoseare absorbed by the small intestine in a two-step process involving their uptake across the a
36、pical membrane into the epithelial cell and their coordinated exit across the basolateral membrane.The Na/glucose transporter 1 (SGLT1) is the membrane protein responsible for glucose and galactose uptake at the apical membrane. The exit of all three monosaccharides across the basolateral membrane u
37、ses a facilitated sugar transporter (GLUT2).,Proteins,Action of luminal, brush border, and cytosolic peptidases. Pepsin from the stomach and the five pancreatic proteases hydrolyze proteinsboth dietary and endogenousto single amino acids, AA, or to oligopeptides, (AA) . These reactions occur in the
38、lumen of the stomach or small intestine. Various peptidases at the brush borders of enterocytes then progressively hydrolyze oligopeptides to amino acids. The amino acids are directly taken up by any of several transporters. The enterocyte directly absorbs some of the small oligopeptides through the
39、 action of the H /oligopeptide cotransporter (PepT1). These small peptides are digested to amino acids by peptidases in the cytoplasm of the enterocyte. Several Na -independent amino acid transporters move amino acids out of the cell across the basolateral membrane,Absorption of whole proteins. Both
40、 enterocytes and specialized M cells can take up intact proteins. The more abundant enterocytes can endocytose far more total protein than can the M cells. However, the lysosomal proteases in the enterocytes degrade 90% of this endocytosed protein. The less abundant M cells take up relatively little
41、 intact protein, but approximately half of this emerges intact at the basolateral membrane. There, immunocompetent cells process the target antigens and then transfer them to lymphocytes, thus initiating an immune response,Lipids,The breakdown of emulsion droplets to mixed micelles,Micellar transpor
42、t of lipid breakdown products to the surface of the enterocyte. Mixed micelles carry lipids through the acidic unstirred layer to the surface of the enterocyte. 2-MAG, fatty acids, lysophospholipids, and cholesterol leave the mixed micelle and enter an acidic microenvironment created by an apical Na
43、-H exchanger. The acidity favors the protonation of the fatty acids. The lipids enter the enterocyte by (1) nonionic diffusion, (2) incorporation into the enterocyte membrane (collision), or (3) carrier-mediated transport.,Re-esterification of digested lipids by the enterocyte and the formation and
44、secretion of chylomicrons. The enterocyte takes up short- and medium-chain fatty acids and glycerol and passes them unchanged into the blood capillaries. The enterocyte also takes up long-chain fatty acids and 2-MAG and resynthesizes them into TAG in the SER. The enterocyte also processes cholestero
45、l into cholesteryl esters and lysolecithin into lecithin. The fate of these substances, and the formation of chylomicrons, is illustrated by steps 1 to 8.,Calcium,Active Ca uptake in the duodenum. The small intestine absorbs Ca by two mechanisms. The passive, paracellular absorption of Ca occurs thr
46、oughout the small intestine. This pathway predominates, but it is not under the control of vitamin D. The second mechanismthe active, transcellular absorption of Ca occurs only in the duodenum. Ca enters the cell across the apical membrane through a channel. Inside the cell, the Ca is buffered by bi
47、nding proteins, such as calbindin, and is also taken up into intracellular organelles, such as the endoplasmic reticulum,Iron,Absorption of nonheme and heme iron in the duodenum. The absorption of nonheme iron occurs almost exclusively as Fe , which crosses the duodenal apical membrane through DMT1,
48、 driven by a H gradient, which is maintained by Na-H exchange. Heme enters the enterocyte by an unknown mechanism. Inside the cell, heme oxygenase releases Fe , which is then reduced to Fe . Cytoplasmic Fe then binds to mobilferrin for transit across the cell to the basolateral membrane. Fe probably exits the enterocyte through basolateral ferroportin. The ferroxidase activity of hephaestin converts Fe to Fe for carriage in the blood plasma bound to transferrin.,Summary,General properties of GIStomachPancreaSmall and large intestineAbsorption,End.,
