Gastroduodenal Mucosal Barrier PDF

Section 7: Gastroduodenal Mucosal Barrier / Pathophysiology of Vomiting I. The gastroduodenal mucosal barrier -protects epitehlium from gastric acid -Maintained by 3 physiological systems A. Alkaline mucus barrier 1. Secretion of mucus layer secreted from...

Section 7: Gastroduodenal Mucosal Barrier / Pathophysiology of Vomiting I. The gastroduodenal mucosal barrier -protects epitehlium from gastric acid -Maintained by 3 physiological systems A. Alkaline mucus barrier 1. Secretion of mucus layer secreted from surface mucus (foveolar) cells 2. Secretion of HCO3 secreted from surface mucus cells into mucus layer Stomach: Cl-/HCO3- exchange by surface epithelium Fig. 28 Duodenum: CFTR and Cl-/HCO3- Exchange HCO3- neutralizes H+ entering the mucus B. High rate of mucosal blood flow 1. Supports metabolic rate of epithelial cells and source of HCO3- 2. Removes H+ crossing tight junctions H+ ions diluted and neutralized by the extracellular fluid (ECF) buffer system (bicarbonate, phosphate, and plasma proteins) 51  C. Epithelial cell barrier, restitution and turnover Occurs throughout the GI tract where there is simple columnar epithelium 1. Cell + Tight Junctions Restricts exposed apical/luminal surface 2. Rapid cell turnover 3-5 Days 3. Restitution after damage Occurs within minutes after damage Fig. 29. Superficial damage and epithelial restitution. 1. Epithelial Damage 2. columnar cells adjacent to wound differentiation to squamous like cells covers exposed surface stimulated by prostglandins (PGs) E.g., the surface between crypt openings normally covered by ~85 cells can be coverd by ~ 15 cells in same process Restitution: Columnar cells adjacent to wound de-differentiate (become squamous-like) to cover exposed submucosa. 52 Prostaglandins are Generated by Cell Damage phospholipase A2 53 D. Barrier regulation by local prostaglandins - Local damage of GI epithelium (by acid, abrasion) and underlying submucosal elements (particularly, fibroblasts) result in the liberation of cellular phospholipase A which generates arachadonic acid from cell membranes. Cells containing cyclooxygenase I and II (COX1 and COX2) generate prostaglandins from arachadonic acid. Prostaglandins resulting from COX1 activity stimulate all three physiological barriers, whereas, prostaglandins resulting from COX2 activity are important in pain perception: 1. Damage → phospholipase A → releases arachidonate→ a. ‘protective’ prostaglandins formed by COX1 activity increased alkaline mucus production, blood flow, and restitution b. ‘pain perception’ prostaglandins formed by COX2 activity 2. Ulcerogenic action of nonsteroidal antiinflammatory drugs (NSAIDS) non-specific NSAIDs: aspirin, phenylbutazone 'bute', ibuprofen inhibit both COX: pain relief, but decrease alkaline mucus production, blood flow and restitution COX-2-specific inhibitors: Rimadyl (carprofen) for dogs pain relief without loss of preotective PGs humans: increse myocardial infarction risk due to imbalance of prestacyclin (vasodilator, inhibits platelet aggregation) and thromboxane A2 (vasoconstriction, platelet aggregation) II. Pathophysiology of vomiting A. Species differences Carnivores and omnivores Carnivores, omnivores can vomit Ruminants Physiological: regurgitation of cud Pathological: abomasal. reflux (no overt clinical signs) Horses Horses, Rabbits, Guinea pigs (other rodents) cannot vomit 54  B. Vomiting Reflex 1.Vomiting Center is located in the reticular formation of the medulla. Mediates and directs nausea, retching and vomiting. Fig. 30 4 inputs to the VC strong emotions vertigo, motion sickness Bloodborne toxins BBB more permeable at the CTZ Noxious stimuli in viscera 2. Afferent input to Vomiting Center: Strong emotions can cause vomitting a) Vestibular apparatus vertigo -caused by diseases affecting the inner ear or the vestibular nerve motion sickness - caused by conflicitng visual and vestibluar signals b) Visceral afferents. Irritation and/or spasm of any viscera sends afferent signals. In GI tract: Stomach Intestine Pharynx trauma, inflammation, infection, toxins Peritoneum Bile ducts (and gall bladder) c) Blood-born toxins via chemoreceptor trigger zone (CTZ). CTZ located in area postrema (has minimal blood-brain barrier) Several sources of circulating toxins Absorbed through the GI tracts, skin or respiratory tract Endogenous inflammatory mediators released by WBCs Infection - toxins and inflammatory mediators Parenteral drug administration 'around' + 'gut" = drugs not given via oral route (e.g., injection) d) Higher CNS centers (human emotions) 55  Directed by VC C. Process of Vomition (Efferent output = Nausea, retching and vomiting) There are 3 stages of vomiting, which usually occur sequentially Stages: 1. Nausea - CNS experience, salivation, proximal stomach muscle relaxes, and reverse peristalsis of duodenum and jejunum. Reverse peristalsis of duodenum Salivation: VC near salivary nuclei content > bile in stomach ( green- 2. Retching - (Dry heaves) - Preparatory maneuver to vomition. gold color in vomit) Stomach relaxes, pylorus contracts no oral or aboral flow from stomach Contraction of abdominal muscles increased intrabdominal pressure Result: favorable pressure gradient Forced inspiratory movement against a closed glottis decreased intrathoracic pressure from stomach to the esophagus 3. Vomition - Proceeds from retching movements. Sustained pyloric contraction Sustained abdominal mm. contraction + Forced inspiratory movement against a closed glottis LES - lower esophgeal sphnicter Cardia moves cranially, LES relaxes and opens to low pressure in esophagus Projectile vomiting: Vomiting without proceeding through nausea or retching Regurgitation: A physiological event in rumination (distinct from vomition) Involves some of the same muscle contraction for pressure gradients Includes esophageal reverse peristalsis D. Metabolic consequences of protracted vomiting e.g. dog with pyloric obsruction With protracted vomiting: Hypovolemia from loss of isotonic, acidic fluid in vomitus. 1. EARLY STAGE: Metabolic alkalosis a) Loss of gastric HCl with strong alkaline tide (blood pH increases) b) Hypokalemia ensues due to K+ loss in vomitus and urine (latter accentuated by aldosterone action at distal tubule) c) Shift of H+ into cells as K+ leaches out 2. LATE STAGE: Metabolic acidosis Advanced hypovolemia → Decreased tissue perfusion → Anaerobic glycolysis → Systemic acidosis 56  EARLY STAGE Fluid therapy directives for protracted vomiting Objectives: 1. Name the 3 physiological systems that make the gastroduodenal mucosal barrier 2. Know the source of bicarbonate in the mucus layer. 3. How does a high rate of mucosal blood flow support the barrier. 4. Describe the process and time course of epithelial restitution and turnover. 5. What is the role of prostaglandins in maintaining the barrier? 6. Know the afferent inputs to the vomiting center. 7. Describe the process of vomition. 8. What are the metabolic consequences of vomiting and how do they develop? Related Questions: 1. What differences in fluid therapy (ionic constituents) are necessary for hypovolemia due to vomiting as compared to hypovolemia due to water deprivation? 2. What are the stimuli to increase circulating aldosterone? 57