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The gastric secretions consist of:■HCl: Digests food, kills ingested bacteria, converts inactive pepsinogens to pepsins.Acid secretion is important for the indiscriminate digestionof ingested matter. However, because of its corrosive nature,there are multiple factors that regulate its secretion fromparietal cells. One factor that keeps HCl secretion undercontrol is parietal cell morphology. Stimulated parietalcells are well organized, with tubulovesicles fusing with theplasma membrane to form intricate canaliculi that increasesurface area for secretion of H+. In contrast, unstimulatedGastrointestinal Secretions275CardiacglandsParietal Mucouscell(neck) cellus (high muM ucci n)acrdiCa nezoChief(zymogen)cellMucus (low mucin)Sa livaryaVagusnervemsey laPepsinoStarchPepsinngel–+ CHw mucincus (lo)Mucus (high mucinMu)GastrinFundic (gastric)glandsDextrinsMaltoseMilkProteinPyloricglandsB12icnstri tornI acfFatPeptidesFundiczoneMucus (low mucin)Mucus (high mucin)CurdsPylzo oricneIntermzo ediane teFigure 23.4 Digestion in the Stomach The stomach secretes concentrated HCl, which breaksingested food into smaller fragment and activates the enzymes pepsin and lipase, to digest proteins andfats, respectively.
The parietal cells, which secrete HCl, also secrete the protein intrinsic factor, which bindsto vitamin B12 to prevent the vitamin’s digestion by pancreatic proteases in the small intestine. In general,about 25% of nutrient digestion occurs before the chyme reaches the duodenum.cells have less surface area exposed to the luminal surfaceof the gastric pits, keeping potential H+ secretion minimal(Fig. 23.6).Parietal cells secrete H+ against a million-fold concentrationgradient in the lumen. The gradient is maintained by tightjunctions, which prevent H+ leak back into the blood.
Thetransport of H+ against the gradient is accomplished by theapical H+/K+ ATPase, or proton, pump. This active antiportpump is the rate-limiting step in H+ transport and is the siteof regulation of acid secretion. Key aspects of acid productionand secretion include the following:■The production of H+ from intracellular conversion ofCO2 to carbonic acid in the reaction (CO2 + H2O →H2CO3 → H+ + HCO3−) (carbonic anhydrase is required276Gastrointestinal PhysiologyMucosal defense mechanismsMucosal mechanismsH+H+MucusPepsinHCO3⫺ H+MucusbicarbonatebarrierPepsinogenpH 1.5pH 2MucusHCO3⫺+H+H2O + CO2(neutralization)EpithelialtightjunctionspH 7HCO3⫺⫺HCO3HCO3⫺H+Gastric mucosa and submucosa protected from chemical injury by mucus-bicarbonate surface barrierthat neutralizes gastric H+ and by epithelial “tight junctions” that prevent H+ access to subepithelial tissueFigure 23.5 Protection of Gastric Mucosa Thick mucus from the surface epithelial cells traps thesecreted bicarbonate on the surface of the gastric mucosa.
The bicarbonate-containing mucus layer protectsthe cells from the caustic acid (pH ∼1.5), keeping the pH at the cell surface ∼7.0.■■■for this conversion). H+ is then available for secretion bythe proton pump.The entry of chloride into the cells via the HCO3−/Cl− exchanger at the basolateral membrane, anddiffusion of chloride into the lumen of the pit throughthe apical membrane (down its concentrationgradient).The exit of HCO3− from the cell into the blood via basolateral HCO3−/Cl− exchangers.
In the actively secretingparietal cell, the large amount of HCO3− entering theblood is described as an alkaline tide.The movement of potassium back into the lumen withCl−.This process primarily produces HCl in the lumen but alsoproduces some KCl. Regulation of acid production takes placethrough stimulation and inhibition of the proton pump,which is the target for most therapeutic interventions toreduce acid secretion (for gastroesophageal reflux disease[GERD], ulcers, etc). Proton pump inhibitors (PPI) such asomeprazole and histamine H2 blockers (ranitidine, cimetidine) are used for this purpose.Constituents of the gastric juices vary with the rate of secretion (see Fig. 23.6). Quiescent, nonstimulated cells producefluid at a low rate; the fluid contains higher levels of Na+and Cl− (more bufferlike) and low concentrations of H+.Gastrointestinal Secretions277160[Cl⫺]140[H+]LumenCO2CO2H2OCarbonicanhydrase(Alkaline tide)HCO3⫺CI⫺K+Na+H2OH2OH2CO3 H O2HCO3⫺+H+Na+ -K+-ATPaseNa+H2OH+-K+-ATPase(proton pump)K+OH⫺+ H+H+CI⫺K+CI⫺K+HCI160 mM/LKCI17 mM/LConcentration (mM)Metabolism120100806040200[K+][Na+]021Rate of secretion (mL/min)Gastric fluid ion concentration asa function of gastric secretion rateParietal cell mechanisms of acid (H+) secretion involve series of chemical exchanges across basal membrane, withfinal active exchange of H+ for K+ mediated across apical (secretory) membrane by H+-K+ ATPase (proton pump).Figure 23.6 Parietal Cell HCl Production The apical H+/K+ ATPase (proton pump) causes the activesecretion of H+ into the lumen of the gastric pits.
This combines with secreted Cl− to form concentrated HCl.HCl production is stimulated by vagal efferent fibers, gastrin, and histamine, which are active when there isfood in the stomach. The H+/K+ ATPase is the target for proton pump inhibitors (PPI) to decrease gastricacid release in patients with GERD or ulcers.However, when cells are stimulated, Na+ concentrations dropand H+ concentrations increase in the juice, producing moreHCl.Several factors stimulate acid secretion:■Regulation of Gastric Acid SecretionThere are three phases of gastric acid secretion:■■■Cephalic phase: Food in the mouth initiates vagal releaseof acetylcholine (ACh) at the parietal cell, stimulatingacid secretion.
Vagal fibers also terminate on enterochromaffin-like (ECL) cells and G-cells, stimulating histamine and gastrin secretion, respectively; histamineand gastrin promote acid secretion.Gastric phase: Stretch, initiated by food in the stomach,releases gastrin from antral G-cells. The gastrin in thebloodstream circulates back to the stomach, stimulatingthe proton pump of the parietal cells. At the same time,the vagus also stimulates the proton pump directly, aswell as by increasing gastrin-releasing peptide (GRP)and histamine, which also act on the pump.Intestinal phase: When chyme enters the duodenumand jejunum, hormones are released that feed back toregulate acid secretion (see following).■■■■■The vagus acts directly at parietal cells and indirectly through stimulation of gastrin and histaminerelease and inhibition of local somatostatin release(Fig. 23.7).Histamine, from ECL cells, diffuses through the mucosato act on adjacent parietal cells.Gastrin, carried through the blood, acts directly on parietal cells.Insulin, carried through the blood, acts directly on parietal cells and promotes HCl secretion.Caffeine (a phosphodiesterase inhibitor) increasescAMP in the parietal cells, increasing proton pumpactivity.Stress, although not well understood, appears to increaseacid secretion in certain people and may be a cofactorin ulcer formation (with Helicobacter pylori).Several factors inhibit acid secretion:■Somatostatin (SS), released from endocrine cells in thegastric pit, acts in a paracrine manner on the parietalcells, as well as on G-cells to inhibit gastrin.278Gastrointestinal PhysiologyAcetylcholineParietalcellLumenCa2+ECL cellParasympatheticHistamineAdenylatecyclaseH+cAMPK+H+/K+-ATPaseATPGastrinCa2+GastrinG cellthrough blood...Figure 23.7 Signal Transduction Mechanisms Regulating HCl Secretion Stimulation of theproton pump can be achieved by both calcium and cAMP-mediated messenger systems.■■■Glucose insulinotropic peptide or gastric inhibitory peptide(GIP), released from the duodenum and jejunum, actsdirectly on the parietal cells.Secretin, released from the duodenum and jejunum, actsat the G-cells to suppress gastrin.Peptide YY, released from various areas of the GI tractin response to fats, helps shut off acid and pancreaticsecretions when chyme is leaving the upper GI tract.
Theeffects on gastric acid may be through suppression ofACh release from cholinergic fibers, and/or stimulationof paracrine somatostatin.While these factors regulate acid secretion, it is importantto understand that they are not all-or-nothing events—forthe most part they work in concert to modulate the amountof acid being secreted during the digestive period. Thus,for example, while the vagus, gastrin, and histamine are stimulating acid secretion, secretin works to moderate gastrinrelease, and somatostatin and GIP act on the parietal cells,keeping acid secretion at a reasonable rate.
The dynamicnature of the system is critical to proper function. Onereason that potentiation of acid secretion can occur isthat various factors use different second messenger systems(see Fig. 23.7).SECRETIONS FROM THE SMALL INTESTINE:BUFFERS, ENZYMES, AND HORMONESThe crypts of Lieberkühn, located at the bottom of the villi inthe small intestine, have a variety of cell types that produceand secrete buffers, enzymes, and hormones that facilitatedigestion and absorption of the nutrients in the chyme(Fig. 23.8). Brunner’s glands are located in the duodenumand secrete thick mucus, which helps to protect the early partof the small intestine from the acidic chyme leaving thestomach.
These glands are stimulated by secretin and activityof the vagus. The Paneth cells are deep in the crypts and arestimulated by secretin to secrete ions and water, which bufferthe chyme. They also secrete lysozyme, which has antimicrobial actions. Goblet cells are located throughout the smallintestine and secrete mucus. Cells also release the enzymeenterokinase, which cleaves the inactive zymogen trypsinogen, forming the active enzyme trypsin. This occurs in theduodenum, activating the powerful protease in the presenceof chyme.The small intestine produces and secretes a variety ofendocrine hormones that regulate digestion and motility(Table 23.3; the major actions of the hormones are in bold).The effects on digestion are detailed in Chapter 26.Gastrointestinal SecretionsCLINICAL CORRELATEUlcersUlcerations were thought to result mainly from ingestion ofNSAIDs (nonsteroidal anti-inflammatory drugs such as aspirin)and stress until about 25 years ago, when Australian investigators discovered Helicobacter pylori residing in the gastric andduodenal mucosa of patients with gastric and duodenal ulcers.
Itis now known that H. pylori accounts for almost all non-NSAID–related gastric ulcers and nearly all duodenal ulcers. How can thebacteria live in the acidic (pH 2) environment of the stomach? H.pylori is resistant to HCl and can burrow into the mucosal layerbecause it secretes urease, which breaks urea into CO2 + ammonia(NH3). This disrupts the bicarbonate–mucus layer protecting thegastric mucosa and allows acid and pepsins to infiltrate themucosa, initiating ulcerations. Interestingly, while most people279have the bacteria (fecal-oral contamination from food or water),a critical number of bacteria must be present to initiate enoughurease production to disrupt the mucosa and expose the epithelium to ulceration. Treatment is with antibiotics (long term) andproton pump inhibitors (PPIs).NSAIDS, including aspirin, ibuprofen, and similar drugs, can alsocause gastric ulcers.
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