Gastric Mucosal Defense Research Articles

Gastric mucosal defence mechanisms: a brief review.

In the stomach several mucosal defence mechanisms protect the stomach against hydrochloric acid and noxious agents. The pre-epithelial protection is made up by the mucus-bicarbonate barrier. Mucus and bicarbonate, secreted by mucus cells, create a pH gradient maintaining the epithelial cell surface at near neutral pH. In humans, secretion of bicarbonate is an active process and is activated by vagal stimulation and fundic distension. Several mechanisms at the epithelial cell level contribute to an intact mucosal barrier. Surfactants in apical cell membranes prevent water-soluble agents in the gastric lumen from reaching and damaging the epithelium. Nonprotein sulphydryls in the epithelium are capable of binding reactive free radicals. Rapid cell turn-over and the process of restitution contribute to an intact epithelial lining. In subepithelial protection, mucosal blood flow is essential in supplying the epithelium with nutrients and oxygen and for disposal of hydrogen ions and noxious agents permeating the mucosa. Prostaglandins may maintain blood flow and prevent vascular endothelial injury caused by ethanol. Several agents have been established as protective for the gastric mucosa. Prostaglandins possess direct cytoprotective actions, whilst sucralfate, aluminium containing antacids, carbenoxolone and bismuth are mild irritants that induce liberation of endogenous prostaglandins of the mucosa.

Therapeutic goals and treatment options for prevention of stress ulcer syndrome

Stress ulcer syndrome, the occurrence of acute upper gastrointestinal bleeding or perforation from stress-related mucosal damage, is a significant cause of morbidity and mortality in critically ill patients. The mortality rate in critically ill patients who have bled from stress ulcers ranges from 50 to 77 percent, whereas the mortality rate for similar patients without stress ulcer bleeding ranges from 9 to 22 percent. The mortality rate may be as high as 90 percent in patients with clinically overt bleeding; as many as one-third of these deaths can be directly related to bleeding. Prophylactic therapy for prevention of stress ulcer bleeding is based on three premises: (1) morbidity and mortality related to stress ulcer syndrome are significant; (2) the population at risk can be identified prior to bleeding; and (3) therapy that decreases gastric acidity or improves gastric mucosal defense mechanisms will prevent ulcer formation or progression to bleeding. A review of prospective clinical studies utilizing prophylactic therapy in critically ill patients and patients undergoing surgery revealed a 17 percent overall bleeding rate for placebo groups compared with lower bleeding rates for antacid- and histamine (H 2)-receptor-antagonist-treated groups (4 and 7 percent, respectively). Studies varied greatly in definition of bleeding, dosage regimens, and gastric pH goals. The need to measure gastric pH during treatment is controversial, and the optimal pH goal and the length of time for which it must be maintained remain unknown. Controversy exists as to the best therapeutic option for prophylaxis of stress ulcer syndrome, but when prevention of clinically significant bleeding is the therapeutic goal, antacids and H 2-receptor antagonists appear to be equally efficacious.

Gastric mucosal defence mechanisms

Gastric mucosal defence mechanisms

Mucosal coating agents and other nonantisecretory agents. Are they cytoprotective?

Gastric cytoprotection is protection against gross and histological gastric mucosal injury by a mechanism other than inhibition of neutralization of gastric acid secretion. Animal studies have shown that a variety of agents afford such a protective effect. With some of these agents, a similar protective effect has been shown in man. This protective effect must be distinguished from an action that enhances healing of an already established mucosal lesion as an ulcer. It is yet to be established that the cytoprotective effect of an agent enhances ulcer healing. Agents other than prostaglandins that have been shown to possess such a cytoprotective effect in animals are reviewed. Some, such as sucralfate, act via stimulation of endogenous prostaglandin synthesis, while others, such as DeNol, neomycin, and meciadanol, do not. Investigation of the mechanism through which these agents enhance gastric mucosal defense is a fertile field for investigation.

Campylobacter pyloridis degrades mucin and undermines gastric mucosal integrity

The role of Campylobacter pyloridis, a spiral bacteria associated with gastritis and peptic ulcers in weakening the mucus component of gastric mucosal barrier was investigated. The colonies of bacteria, cultured from antral mucosal biopsies of patients undergoing gastroscopy, were washed with saline, passed through sterilization filter and the filtrate was examined for protease and glycosylhydrolase activities. The obtained results revealed that the filtrate exhibited a strong proteolytic activity not only towards the typical protein substrates such as albumin but also towards gastric mucin. Optimum enzymatic activity for degradation of mucin was attained at pH 7.0 and the protease activity was found in a low m.w. (less than 50K) protein fraction. The filtrate showed little glycosylhydrolase activity and did not cause the hydrolysis of mucin carbohydrates. The data suggest that C pyloridis infection weakens the gastric mucosal defense by causing proteolytic degradation of mucin component of the protective mucus layer.

Protective effect of exogenous phospholipid on aspirin-induced gastric mucosal injury

The protective effects of exogenous phospholipid on aspirin-induced gastric mucosal injury were examined in a canine chamber model which provided two separate segments of mucosa supplied by a single vascular pedicle. In each dog, one segment was treated with a suspension of surface-active phospholipid, similar in composition to that normally present in the gastric mucosa, whereas the other segment served as the control. Pretreatment of the test segments significantly prevented aspirin-induced disruption of the mucosal barrier as evidenced by an increase in potential difference and a decrease in acid back-diffusion and sodium ion and potassium ion flux. These findings were associated with a marked reduction in the degree of mucosal injury. Our results support the recent hypothesis that surface-active phospholipid plays an important role in gastric mucosal defense against the damaging effects to luminal acid.

Gastric mucosal defence mechanisms

Gastric mucosal defence mechanisms

Gastric Bleeding and/or (?) Enteral Feeding

Upper gastrointestinal bleeding from stress ulceration is a serious complication of critical illness which is associated with increased morbidity and mortality. 1 Zinner MJ Zuidema GD Smith PL Mignosa M The prevention of upper gastrointestinal tract bleeding in patients in an intensive care unit. Surg Gynecol Obstet. 1981; 153: 214-220 PubMed Google Scholar , 2 Harris (Pingleton) SK Bone RC Ruth WE Gastrointestinal hemorrhage in patients in a respiratory intensive care unit. Chest. 1977; 72: 301-304 Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar , 3 Schuster DP Rowley H Feinstein S McGue MK Zukerman GR Prospective evaluation of the risk of upper gastrointestinal bleeding after admission to a medical intensive care unit. Am J Med. 1984; 76: 623-630 Abstract Full Text PDF PubMed Scopus (191) Google Scholar Efforts to prevent gastric bleeding have centered on prevention of stress ulceration. Stress ulcers are caused by a complex interaction of systemic, tissue and luminal factors which destroy the ability of the intact gastric mucosa to maintain homeostasis. 4 Silen W Pathogenetic factors in erosive gastritis. Am J Med. 1985; 79: 45-48 Abstract Full Text PDF PubMed Scopus (22) Google Scholar Preservation of gastric mucosal integrity is a dynamic process dependent upon normal gastric blood flow, systemic acid-base balance and normal metabolic and secretory state of the mucosa. Experimental evidence suggests gastric acid plays a key role in the formation of gastric erosions, not from excessive acid secretion, but rather from a temporary failure of gastric mucosal defense mechanisms to deal with the acid present. 5 Marrone GC Silen W Pathogenesis, diagnosis and treatment of acute gastric mucosal lesions. Clin Gastroenterology. 1984; 13: 635-649 PubMed Google Scholar Therefore, prophylactic measures have centered on neutralizing gastric acidity with antacids and decreasing gastric acid secretion with histamine2-receptor blockers, such as cimetidine or ranitidine. An array of clinical studies suggest antacids are superior in elevating gastric pH and decreasing gastric bleeding. 1 Zinner MJ Zuidema GD Smith PL Mignosa M The prevention of upper gastrointestinal tract bleeding in patients in an intensive care unit. Surg Gynecol Obstet. 1981; 153: 214-220 PubMed Google Scholar , 2 Harris (Pingleton) SK Bone RC Ruth WE Gastrointestinal hemorrhage in patients in a respiratory intensive care unit. Chest. 1977; 72: 301-304 Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar , 6 Priebe HJ Skillman JJ Bushnell LS Long PC Silen W Antacid versus cimetidine in preventing acute gastrointestinal bleeding. N Engl J Med. 1980; 302: 426-430 Crossref PubMed Scopus (263) Google Scholar , 7 Martin LF Staloch DK Simonwitz DA Failure of cimetidine prophylaxis in the critically ill. Arch Surg. 1979; 114: 492-496 Crossref PubMed Scopus (42) Google Scholar However, recent data indicate that cimetidine may prevent progression of established stress ulceration. 8 Peura DA Johnson LF Cimetidine for prevention and treatment of gastroduodenal mucosal lesions in patients in an intensive care unit. Ann Intern Med. 1985; 103: 173-177 Crossref PubMed Scopus (154) Google Scholar

HEMORRHAGE FROM GASTRITIS IN THE EARLY STAGE AFTER ESOPHAGEAL TRANSECTION WITH DEVASCULARIZATION

Hemorrhage from gastritis occurring within the first month after direct procedure for esophageal varices was studied. Three of 473 cases (0.6%) bled from endoscopically diagnosed gastritis. All 3 cases underwent the one-stage combined procedure of transthoracic esophageal transection and transdiaphragmatic splenectomy and paraesophagogastric devascularization. However, they did not undergo pyloroplasty, as is our usual procedure with paragastric devascularization. Only 4 cases underwent a one-stage operation without pyloroplasty, and 3 of them (75%) had complicating hemorrhagic gastritis. A possible cause of the hemorrhagic gastritis is a combination of decreased gastric mucosal defense factors with changes in gastric mucosal blood flow due to wide paragastric devascularization and increased gastric mucosal attack factors with disturbance of gastric emptying due to vagotomy. It may be conculuded that these changes remain only a short time after operation, because recurrent bleeding has not occurred in the 3 cases.

Gastric mucosal defence mechanisms.

Gastric mucosa has a particular ability to resist acid/peptic digestion. The nature of the presumed barrier to acid and pepsin has been elusive but recent work suggests that a combination of mechanisms is likely to be involved. Amongst these the mucus gel layer combined with secretion of alkali by the surface epithelium is likely to form a first line defence. The demonstration of a pH gradient within the mucus gel layer supports such a hypothesis. Agents which damage the mucosa such as aspirin and bile salts inhibit the maintenance of the pH gradient allowing the luminal surface of the epithelium to become more acid. Prostaglandins enhance this pH gradient, an observation which may be relevant to the protective properties of prostaglandins. This alkaline zone can be compromised by high levels of luminal acidity and it thus has a limited capacity to prevent acid reaching the mucosa. The local microcirculation is of importance in maintaining surface epithelial metabolic integrity and interstitial fluid bicarbonate may be important in neutralising any acid which may reach the subepithelial layers. This may in part explain the ability of an actively secreting gastric epithelium to resist damage to a greater extent than a resting mucosa. Recent exciting work has focussed on the ability of gastric epithelium to reform by a process which has been termed restitution, after acute mucosal damage. This process appears to be rapid and occurs within an hour or so. Repeated rapid repair may be a common occurrence in the maintenance of mucosal integrity. Finally, it has been proposed that a hydrophobic property of surface epithelium in the stomach may be relevant to mucosal protection.

Morphology of Rat Gastric Mucosal Damage, Defense, and Restitution in the Presence of Luminal Ethanol

The morphology of ligated rat stomachs filled with absolute ethanol for 1, 7, 15, 30, and 60 min was studied. With interrupted blood circulation, the entire mucosa was destroyed within minutes. With intact circulation, the mucosae remained macroscopically normal or developed visible lesions. Areas with lesions had extensive surface and gland cell disruption and were hemorrhagic and hyperemic. Histologically, nonlesion sites had about 92% of the mucous cells on the surface and upper gastric pits destroyed within 1 min. Detached necrotic cells and an accumulation of an exudate with fibrin fibers formed a thick layer over the damaged mucosal surface. Intact cells from the gastric pits started migrating over the denuded basal lamina and after 7 min about 4% of the surface was reepithelialized. Within the next 8 min there was a sharp increase in mucosal restitution to about 54%. After 30 min 84% of the mucosa was restituted and there was only a slight increase to about 87% after 1 h of continuous exposure to ethanol. After 30 min the ethanol was diluted to about 40% vol/vol. Focal geyserlike eruptions of plasma containing polymerized fibrin were visible at sites of epithelial discontinuity. Restitution of the mucosal surface in the presence of luminal ethanol may be facilitated by the favorable microenvironment created by the thick unstirred layer formed by the mucoid coat of necrotic cells, fibrin, and continued plasma shedding.

Cell loss from human, canine and guinea-pig gastric mucosa measured by DNA radioimmunoassay

A DNA radioimmunoassay, sensitive in the range 25-1000 ng, has been developed to measure gastric mucosal cell loss. Validity of the assay was based on antibody specificity, absence of interference from gastric contents, parallel tracer displacement by dilutions of gastric and standard DNA, and crossover with colorimetric assay. With this assay, gastric DNA shedding was examined in two animal species and man. In the guinea-pig stomach, DNA loss was 20-100 micrograms/h and in the canine Pavlov pouch, 260-580 micrograms/h. In the canine Pavlov pouch stimulation of acid secretion by histamine and exposure to exogenous acid increased DNA output. In the normal human stomach DNA loss was 544 +/- 175 micrograms/h and in duodenal ulcer patients, 649 +/- 225 micrograms/h. DNA radioimmunoassay provides a sensitive and reproducible measure of cell exfoliation from the stomach and may be a useful tool for studying aspects of gastric mucosal defence.

The effect of secretin on canine gastric mucosal HCO 3− production

Recent studies suggest that HCO 3 − production by surface epithelium may protect gastric mucosa against H + back diffusion. Agents shown to increase gastric HCO 3 − include prostaglandins, carbachol, dibutyryl c-GMP, ethanol, Ca 2+, and cimetidine. This study was initiated to evaluate the effect of secretin on gastric mucosal HCO 3 − production. Six dogs with Heidenhain pouches were fasted 24 hr. Each study consisted of nine 15-min periods: three control periods of iv saline infusion; three test periods which followed an iv bolus of 0.15 clin units/kg secretin; and three test periods which followed an iv bolus of 0.30 clin units/kg secretin. The intragastric test solution consisted of 100 m M NaCl, 20 m M mannitol, and 50 m M EPPS buffer; pH was adjusted to 8.0–8.2 using 19 M NaOH. Fifty milliliters test solution was instilled in the pouch and a zero-time sample was taken; after 15 min a final sample was taken, the pouch was rinsed, and the next period begun. HCO 3 −, Na +, K +, and Cl − concentrations were measured as well as transmucosal electrical potential difference (PD) changes and changes in volume, pH, and osmolality. [ 14C]PEG was utilized to measure residual volume. In the first 15-min period following each secretin bolus, significant ( P < 0.05) increases in intraluminal gastric HCO 3 − occurred. However, doubling the secretin dose did not significantly increase the measured HCO 3 − when compared to the lower dose. Also undetectable were changes in ionic fluxes accompanying the increases in intraluminal HCO 3 − which might have suggested a mechanism of the HCO 3 − production. In addition to its previously described properties of acid inhibition and gastric mucus stimulation, this study demonstrates that secretin also induces production of gastric HCO 3 −. The clinical significance of these modest increases remains to be determined but they may contribute to gastric mucosal barrier defense.

Cimetidine-induced bicarbonate production in canine gastric pouches

Secretion of HCO 3 − into a mucus-gel “unstirred layer” has been proposed as part of the gastric mucosal defense system. Cimetidine has a cytoprotective effect on salicylate-challenged gastric mucosa independent of its acid-inhibiting property. This study was done to (1) evaluate whether cimetidine increases gastric mucosal HCO 3 and to (2) ascertain if ionic shifts accompany the HCO 3 − to explain the mechanism of its production. Six dogs with Heidenhain gastric pouches were fasted 24 hr prior to testing. Pouch access was provided by a cannula fitted with an airtight apparatus for test solution instillation and removal and transmucosal potential difference (PD) measurement. A test solution composed of 175 m M mannitol, 25 m M NaCl, and 50 m M EPPS buffer was used, its pH adjusted to above 8.0; 14C-labeled polyethylene glycol was added for volumetric determinations. Nine 15-min periods comprised each test: four control periods of iv saline infusion; a fifth period when an iv cimetidine bolus was given; and four test periods when doses of 2.5, 5, or 10 mg/kg/hr cimetidine were infused iv. Test solution (50 ml) was placed in the pouch and an initial sample taken; 15 min later a final sample was taken, the pouch rinsed, and the next period begun. Concentrations of HCO 3 −, Na +, K +, and Cl − were determined for each sample as well as changes in osmolality, pH, volume, and PD. Mean net HCO 3 − increased from 79 μmol/15 min during saline infusions to 109, 124, and 123 μmol/15 min with 2.5, 5, and 10 mg/kg/hr cimetidine iv; all are significantly increased compared to saline controls ( P < 0.01). None of the other measured parameters changed significantly after cimetidine infusion. Cimetidine causes modest but significant increases in gastric mucosal HCO 3 −. The clinical role, if any, of these increases in HCO 3 − in gastric mucosal defense remains to be determined.

Measurement of glycoprotein content and cell kinetics in preulcerous gastric mucosa.

In an attempt to evaluate the role of gastric mucosal defense factors in ulcerogenesis, we measured the levels of glycoproteins in the mucosa as well as mucosal cell turnover in the preulcerous phase and compared these parameters to the normal mucosa in the same animal. Ovalbumin-presensitized Praomys (Mastomys) natalensis were challenged in the gastric wall with ovalbumin and a gastric ulcer developed at the challenge site 3 days later as a result of a mucosal anaphylactic reaction. This model enabled us to study the events occurring at the site of a future ulceration. Gas-liquid chromatographic determination of mucosal glycoproteins showed that the normal and preulcerous mucosae had similar levels. Cell turnover, determined by [3H]thymidine incorporation, was stimulated as a result of the preulcerous anaphylactic reaction at 24 hours postchallenge whereas at 48 hours the values were not different from those obtained in controls. These results suggest that the pathogenesis of anaphylactic gastric ulcer involves a change in cell turnover but no changes in the production of gastric mucus.

Gastric mucosal defense mechanisms: Effects of salicylate and histamine

Some of the recent concepts about the gastric mucosal defense mechanisms against damage by luminal acid and the effects of histamine and salicylate on these mechanisms are reviewed. The mucosal barrier to acid appears to consist of at least two physiologic components: a permeability mechanism and a metabolic mechanism related to cellular bicarbonate production as a result of acid secretion. In the absence of salicylate, histamine appears to exert some protection by affecting both mechanisms, but in the presence of salicylate, histamine's protective effect is limited to altering mucosal permeability. The actions of salicylate on the gastric mucosa are complex, related in part to the concentration of salicylate and the pH of the luminal fluid. The damaging effects of salicylate appear to be related more to the concentration of acid in the lumen than to the lipid solubility of the drug. Salicylate increases permeability regardless of pH; the increase is initially selective for cations and subsequently becomes nonselective, involving both cations and anions. Although both low and high concentrations of salicylate increase mucosal permeability to hydrogen ions, only high concentrations of salicylate affect cellular bicarbonate production.

Effects of prostaglandins on the stomach and the intestine

The stomach is in a state of continuous exposure to potentially hazardous agents. Hydrochloric acid together with pepsin constitutes a major and serious threat to the gastric mucosa. Reflux of alkaline duodenal contents containing bile and pancreatic enzymes are additional important injurious factors of endogenous origin. Alcohol, cigarette smoking, drugs and particularly aspirin and aspirin-like drugs, and steriods are among exogenous mucosal irritants that can inflict mucosal injury. The ability of the stomach to defend itself against these noxious agents has been ascribed to a number of factors constituting the gastric mucosal defense. These include mucus and bicarbonate secreted by surface epithelial cells, prostaglandins, sulfhydryl compounds and gastric mucosal blood flow. The latter is considered by several researchers to be of paramount importance in maintainig gastric mucosal integrity. The aim of this paper is to review the experimental and clinical data dealing with the role of mucosal blood flow and in particular the microcirculation in both damage and protection of the gastric mucosa.