Ethanol-induced Gastric Mucosal Injury Research Articles

Role of mucus and prostaglandins in the gastric mucosal protective actions of sucralfate against ethanol-induced injury in the rat

This study investigated the relationship between the protective effect of sucralfate against ethanol-induced gastric mucosal injury in the rat and the effects of sucralfate on prostaglandin and mucus synthesis and secretion. Sucralfate at 200, 400, and 800 mg/kg significantly reduced gastric ulceration. Intragastric administration of sucralfate increased luminal mucus and prostaglandin E 2 levels but did not affect prostaglandin or mucus synthesis in gastric mucosal biopsy specimens from sucralfate-treated animals. Pretreatment with indomethacin partially reduced the protective effect of sucralfate. However, sucralfate 200 mg/kg, a dose that completely prevented ulceration, did not increase the levels of luminal prostaglandin E 2. In vitro incubation with sucralfate did not stimulate mucosal prostaglandin synthesis. Longer-term administration of sucralfate for 48 or 96 hours did not stimulate mucus or prostaglandin synthesis but did increase luminal prostaglandin E 2 and mucus. Although sucralfate increased the gastric juice content of prostaglandin E 2 and mucus, the two did not appear to be mechanistically related, and only mucus release was consistently associated with mucosal protection.

Is cytoprotection by misoprostol against ethanol-induced gastric mucosal injury in man mediated by somatostatin?

Is cytoprotection by misoprostol against ethanol-induced gastric mucosal injury in man mediated by somatostatin?

Protection by metals against ethanol-induced gastric mucosal injury in the rat: Comparative biochemical and pharmacologic studies implicate protein sulfhydryls

Recent evidence suggests a role of endogenous sulfhydryls (SHs) in gastric “cytoprotection.” Because divalent metals bind to or oxidize SH groups, their effect on ethanol-induced gastric erosions was studied. For comparative biochemical studies the SH cysteamine, the glutathione depletor diethylmaleate, and SH alkylating agent N-ethylmaleimide (NEM) were also used. Rats pretreated with CdCl2, ZnCl2, or Cu(NO3)2 6 h before absolute ethanol showed a significant dose-dependent decrease in the mucosal lesions. Copper was effective in preventing the lesions up to 15 min before the ethanol. Iron and manganese were active at 30 min, but not at 6 h before the ethanol lesions. Indomethacin administration decreased the protection afforded by iron, manganese, and cadmium, but did not modify that by lead and copper. N-ethylmaleimide abolished the protection by iron, manganese, and cadmium, but did not affect the protection caused by lead and copper when given after the metals. However, when NEM was given before lead and copper, it diminished the protection. Secretory studies revealed that cadmium and zinc slightly inhibited gastric acid secretion, but a similar reduction of acid output by cimetidine did not decrease the ethanol-induced gastric erosions. Biochemical studies of endogenous SH showed that the protective metals and NEM decreased the glutathione concentration in the nonprotein fraction, whereas these metals diminished and NEM, which antagonizes mucosal protection, elevated the cysteine concentration in the protein fraction of the gastric mucosa. The common factor with the protective agents thus seems to be the blocking of protein SH by binding or oxidation by protective agents. These endogenous SHs may mediate cellular responses to injury.

Protection by metals against ethanol-induced gastric mucosal injury in the rat

Abstract Recent evidence suggests a role of endogenous sulfhydryls (SHs) in gastric cytoprotection. Because divalent metals bind to or oxidize SH groups, their effect on ethanol-induced gastric erosions was studied. For comparative biochemical studies the SH cysteamine, the glutathione depletor diethylmaleate, and SH alkylating agent N-ethylmaleimide (NEM) were also used. Rats pretreated with CdCl 2 , ZnCl 2 , or Cu(NO 3 ) 2 6 h before absolute ethanol showed a significant dose-dependent decrease in the mucosal lesions. Copper was effective in preventing the lesions up to 15 min before the ethanol. Iron and manganese were active at 30 min, but not at 6 h before the ethanol lesions. Indomethacin administration decreased the protection afforded by iron, manganese, and cadmium, but did not modify that by lead and copper. N -ethylmaleimide abolished the protection by iron, manganese, and cadmium, but did not affect the protection caused by lead and copper when given after the metals. However, when NEM was given before lead and copper, it diminished the protection. Secretory studies revealed that cadmium and zinc slightly inhibited gastric acid secretion, but a similar reduction of acid output by cimetidine did not decrease the ethanol-induced gastric erosions. Biochemical studies of endogenous SH showed that the protective metals and NEM decreased the glutathione concentration in the nonprotein fraction, whereas these metals diminished and NEM, which antagonizes mucosal protection, elevated the cysteine concentration in the protein fraction of the gastric mucosa. The common factor with the protective agents thus seems to be the blocking of protein SH by binding or oxidation by protective agents. These endogenous SHs may mediate cellular responses to injury.

Dose-dependent effects of linear and cyclic somatostatin on ethanol-induced gastric erosions: the role of mast cells and increased vascular permeability in the rat

Somatostatin prevents hemorrhagic gastric erosions produced by ethanol. In this paper we describe studies with linear (reduced) and cyclic (oxidized) synthetic somatostatin-14 in the rat model of ethanol-induced gastric mucosal injury. The linear form of somatostatin was more potent at concentrations of 10 −9 to 10 −8 mol per rat than the cyclic isomere. However, at a concentration of 10 −7 mol per rat i.p. injection of linear somatostatin significantly ( P < 0.01) enhanced gastric erosions caused by the alcohol. The area of hemorrhagic mucosal lesions correlated significantly ( r = −0.846) with mast cell depletion in the gastric mucosa of the animals. Increased vascular permeability and mast cell degranulation were also observed after intradermal injection of linear or cyclic somatostatin. The ‘cytoprotective’ as well as the aggravating potency of linear somatostatin may be connected to gastric mucosal mast cell activity in the rat.

Gastric blood flow in ethanol injury and prostaglandin cytoprotection.

Studies performed in the author's laboratory concerning the role of gastric mucosal blood flow in ethanol-induced gastric mucosal injury and prostaglandin cytoprotection are reviewed. Fluorescent in vivo microscopic and hydrogen gas clearance studies revealed total absence of blood flow in the gross ethanol-induced lesions. Prostaglandin pretreatment not only prevented gross lesion formation but flow was present throughout the mucosa. A cytoprotective dose of the prostaglandin analogue did not increase blood flow. Transmitted light in vivo microscopy revealed rapid cessation of blood flow through mucosal microvessels within 1 min of ethanol application. The microvessels remained filled with red blood cells, suggesting an intravascular coagulation phenomenon. Histologic studies revealed no necrotic lesion formation 1 min after ethanol, but increasing necrosis from 10 to 60 min. These findings suggest that the rapid ethanol-induced cessation of blood flow renders the gastric mucosa more susceptible to ethanol injury and prostaglandin acts by preventing this blood flow change.

Gastric mucosal blood flow in rats after administration of 16,16-dimethyl prostaglandin E2 at a cytoprotective dose

The purpose of the present study was to determine whether the gastric cytoprotective effect of a prostaglandin such as 16,16-dimethyl prostaglandin (dmPGE2) is mediated by an increase in mucosal blood flow. Gastric mucosal blood flow was measured in urethane-anesthetized rats by the hydrogen gas clearance technique. In control rats given no ethanol, intragastric administration of dmPGE2 (10 μg/kg body wt) produced a significant reduction (15.3%) in gastric mucosal blood flow 30 min after treatment. This dose of dmPGE2 significantly reduced the formation of the gross gastric lesions produced by absolute ethanol in anesthetized rats. In vehicle-pretreated animals, blood flow was invariably absent in the ethanol-induced mucosal lesion areas. In the nonlesion areas, gastric mucosal blood flow was the same in prostaglandin-pretreated and vehicle-pretreated animals as in control (no ethanol) rats. Thus, although dmPGE2 pretreatment protected against ethanol-induced gastric mucosal injury and prevented the accompanying blood flow stasis, it did not do this by an increase in gastric mucosal blood flow. The protection also is not due to a decrease in flow because, in separate groups of anesthetized rats, a 15% reduction in gastric mucosal blood flow induced by either hemorrhage or intravenous vasopressin did not protect the gastric mucosa against absolute ethanol-induced injury. Whether the maintenance of gastric mucosal blood flow is a primary or secondary effect of prostaglandin cytoprotection remains to be determined.

Quantification of ethanol-induced gastric mucosal injury by transmission densitometry

A method to objectively quantify the extent of ethanol-induced gastric lesions has been developed. The method utilizes a transmission densitometer to measure the optical density of the photographic negative of the stomach mucosa. Tissues from ethanol- and untreated animals are compared with tissues from animals pretreated with prostanoids before ethanol; this method permits a reproducible and objective evaluation of mucosal protection. We demonstrate that the optical density is proportional to subjective score and damage, and that the densitometry method differentiates between the protective effect of different doses of 16,16-dimethyl prostaglandin E 2 and natural prostaglandin E 2.

Role of the Adrenal Cortex in Gastric Mucosal Protection by Prostaglandins, Sulfhydryls, and Cimetidine in the Rat

To investigate the possible role of hormones in gastric mucosal protection, the effect of prostaglandin F2 beta, dimercaprol, or cysteamine on ethanol-induced gastric erosions, and of cimetidine on gastric erosions caused by aspirin was studied in intact, adrenalectomized, medullectomized, ovariectomized, or thyroidectomized rats. Cimetidine was administered at a low dose that did not inhibit hydrogen ion secretion. Adrenalectomized animals failed to exhibit the usual mucosal protective response to prostaglandin F2 beta, sulfhydryls, or cimetidine. Ovariectomy or thyroidectomy did not influence mucosal protection with these agents. The inhibition by total adrenalectomy of mucosal protection was not reversed by large intragastric doses or by parenteral administration of prostaglandin F2 beta. Adrenal medullectomy alone significantly diminished (by approximately one-third) ethanol-induced gastric mucosal injury; prostaglandin F2 beta or sulfhydryl drugs produced significant additional protection. Replacement therapy with glucocorticoids (triamcinolone, corticosterone) but not with mineralocorticoids (deoxycorticosterone, 9 alpha-fluorocortisol) restored the cytoprotective effect of prostaglandin F2 beta and sulfhydryls in adrenalectomized rats. The generation of prostaglandin E2- and prostaglandin I2-like activity in the gastric mucosa was unaltered by adrenalectomy. These studies suggest a permissive role for glucocorticoids in gastric mucosal protection induced by prostaglandins, sulfhydryls, and cimetidine.