Pathogenesis Of Gastric Mucosal Damage Research Articles

Modulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis by Helicobacter pylori in immune pathogenesis of gastric mucosal damage.

Helicobacter pylori infection is associated with chronic gastritis, peptic ulcer, gastric carcinoma, and gastric mucosa-associated lymphoid tissue lymphomas. Apoptosis induced by microbial infections is implicated in the pathogenesis of H. pylori infection. Enhanced gastric epithelial cell apoptosis during H. pylori infection was suggested to play an important role in the pathogenesis of chronic gastritis and gastric pathology. In addition to directly triggering apoptosis, H. pylori induces sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in gastric epithelial cells. Human gastric epithelial cells sensitized to H. pylori confer susceptibility to TRAIL-mediated apoptosis via modulation of death-receptor signaling. The induction of TRAIL sensitivity by H. pylori is dependent upon the activation of caspase-8 and its downstream pathway. H. pylori induces caspase-8 activation via enhanced assembly of the TRAIL death-inducing signaling complex through downregulation of cellular FLICE-inhibitory protein. Moreover, H. pylori infection induces infiltration of T lymphocytes and triggers inflammation to augment apoptosis. In H. pylori infection, significant increases in CCR6+ CD3+ Tcell infiltration in the gastric mucosa was observed, and the CCR6 ligand, CCL20 chemokine, was selectively expressed in inflamed gastric tissues. These mechanisms initiate chemokine-mediated T lymphocyte trafficking into inflamed epithelium and induce mucosal injury during Helicobacter infection. This article will review recent findings on the interactions of H. pylori with host-epithelial signaling pathways and events involved in the initiation of gastric pathology, including gastric inflammation and mucosal damage.

The Impact of Asymmetric Dimethylarginine (ADAMA), the Endogenous Nitric Oxide (NO) Synthase Inhibitor, to the Pathogenesis of Gastric Mucosal Damage

This review was designed to provide an update on the role of asymmetric arginine (ADMA), the endogenous inhibitor of nitric oxide (NO) synthase in the pathophysiology of the upper gastrointestinal (GI) tract. Numerous studies in the past confirmed that NO is a multifunctional endogenous gas molecule involved in most of the body organs’ functional and metabolic processes including the regulation of gastrointestinal (GI) secretory functions, motility, maintenance of GI integrity, gastroprotection and ulcer healing. NO is metabolized from L-arginine by enzymatic reaction in the presence of constitutive NO synthase. In upper GI tract, NO acts as a potent vasodilator known to increase gastric mucosa blood flow, regulates the secretion of mucus and bicarbonate, inhibits the gastric secretion and protects the gastric mucosa against the damage induced by a variety of damaging agents and corrosive substances. In contrast, ADMA first time described by Vallance and coworkers in 1992, is synthesized by the hydrolysis of proteins containing methylated arginine amino acids located predominantly within the nucleus of cells. This molecule has been shown to competitively inhibit NO synthase suggesting its regulatory role in the functions of vascular endothelial cells and systemic circulation in humans and experimental animals. Nowadays, ADMA is a potentially important risk factor for coronary artery diseases and a marker of cardiovascular risk. Increased plasma levels of ADMA have been documented in several conditions that are characterized by endothelial dysfunction, including hypertension, hypercholesterolemia, hyperglycemia, renal failure and tobacco exposure. The role of ADMA in other systems including GI-tract has been so far less documented. Nevertheless, ADMA was shown to directly induce oxidative stress and cell apoptosis in gastric mucosal cells in vitro and to contribute to the inflammatory reaction associated with major human pathogen to gastric mucosa, Helicobacter pylori (H.pylori). Infection of gastric mucosa with this germ or H. pylori water extract led to marked increase in the plasma concentration of ADMA and significantly inhibited bicarbonate secretion, considered as one of the important components of upper GI-tract defense system. When administered to rodents, ADMA aggravated gastric mucosal lesions injury induced by cold stress, ethanol and indomethacin and this worsening effect on gastric lesions was accompanied by the significant increase in the plasma level of ADMA. This exaggeration of gastric lesions by ADMA was coincided with the inhibition of NO, the suppression of gastric blood flow and excessive release of proinflammatory cytokine TNF-α. This metabolic analog of L-arginine applied to rats was exposed to water immersion and restraint stress and ischemiareperfusion, causing an elevation of plasma levels of ADMA and gastric MDA content, which is the marker of lipid peroxidation. These effects, including the rise in the plasma levels of ADMA in rats with stress and ischemia-reperfusion-induced gastric lesions, were attenuated by concomitant treatment with L-arginine, the substrate for NO-synthase, and superoxide dismutase (SOD), a reactive oxygen metabolite scavenger added to ADMA. We conclude that ADMA could be considered as an important factor contributing to the pathogenesis of gastric mucosal damage and inflammatory reaction in H. pylori-infected stomach due to inhibition of NO, suppression of GI microcirculation, and the proinflammatory and proapoptotic actions of this arginine analog.

The Impact of Asymmetric Dimethylarginine (ADAMA), the Endogenous Nitric Oxide (NO) Synthase Inhibitor, to the Pathogenesis of Gastric Mucosal Damage

This review was designed to provide an update on the role of asymmetric arginine (ADMA), the endogenous inhibitor of nitric oxide (NO) synthase in the pathophysiology of the upper gastrointestinal (GI) tract. Numerous studies in the past confirmed that NO is a multifunctional endogenous gas molecule involved in most of the body organs' functional and metabolic processes including the regulation of gastrointestinal (GI) secretory functions, motility, maintenance of GI integrity, gastroprotection and ulcer healing. NO is metabolized from L-arginine by enzymatic reaction in the presence of constitutive NO synthase. In upper GI tract, NO acts as a potent vasodilator known to increase gastric mucosa blood flow, regulates the secretion of mucus and bicarbonate, inhibits the gastric secretion and protects the gastric mucosa against the damage induced by a variety of damaging agents and corrosive substances. In contrast, ADMA first time described by Vallance and coworkers in 1992, is synthesized by the hydrolysis of proteins containing methylated arginine amino acids located predominantly within the nucleus of cells. This molecule has been shown to competitively inhibit NO synthase suggesting its regulatory role in the functions of vascular endothelial cells and systemic circulation in humans and experimental animals. Nowadays, ADMA is a potentially important risk factor for coronary artery diseases and a marker of cardiovascular risk. Increased plasma levels of ADMA have been documented in several conditions that are characterized by endothelial dysfunction, including hypertension, hypercholesterolemia, hyperglycemia, renal failure and tobacco exposure. The role of ADMA in other systems including GI-tract has been so far less documented. Nevertheless, ADMA was shown to directly induce oxidative stress and cell apoptosis in gastric mucosal cells in vitro and to contribute to the inflammatory reaction associated with major human pathogen to gastric mucosa, Helicobacter pylori (H.pylori). Infection of gastric mucosa with this germ or H. pylori water extract led to marked increase in the plasma concentration of ADMA and significantly inhibited bicarbonate secretion, considered as one of the important components of upper GI-tract defense system. When administered to rodents, ADMA aggravated gastric mucosal lesions injury induced by cold stress, ethanol and indomethacin and this worsening effect on gastric lesions was accompanied by the significant increase in the plasma level of ADMA. This exaggeration of gastric lesions by ADMA was coincided with the inhibition of NO, the suppression of gastric blood flow and excessive release of proinflammatory cytokine TNF-α. This metabolic analog of L-arginine applied to rats was exposed to water immersion and restraint stress and ischemia-reperfusion, causing an elevation of plasma levels of ADMA and gastric MDA content, which is the marker of lipid peroxidation. These effects, including the rise in the plasma levels of ADMA in rats with stress and ischemia-reperfusion-induced gastric lesions, were attenuated by concomitant treatment with L-arginine, the substrate for NO-synthase, and superoxide dismutase (SOD), a reactive oxygen metabolite scavenger added to ADMA. We conclude that ADMA could be considered as an important factor contributing to the pathogenesis of gastric mucosal damage and inflammatory reaction in H. pylori-infected stomach due to inhibition of NO, suppression of GI microcirculation, and the proinflammatory and proapoptotic actions of this arginine analog.

The role of endotoxin in the pathogenesis of gastric mucosal damage in cirrhotic rats with portal hypertensive gastropathy

Objective To study the role and the mechanism of endotoxin in the pathogenesis of gastric mucosa during portal vein hypertension gastrography (PHG) in the rats with cirrhosis. Methods Rat model for PHG was established by injection of tetrachloride. The animals were injected with endotoxin i.p. at 3 mg/kg and endotoxin antagonist BPI21 i.v. at 2.0 mg/kg. The plasma level of endotoxin as well as the gastric mucosal level of tumor necrosis factor alpha (TNF-α) was measured with azobenzene and ELISA respectively. Furthermore, the pathological changes of the gastric mucosa were studied with HE stainning. Results In rats with PHG, increased endotoxin and TNF-α as well as the gastric pathological lesion were observed. Injection of endotoxin remarkably increased plasma level of endotoxin as well as the gastric mucosal level of tumor necrosis TNF-α and induced more serious gastric lesion. Animals injected with endotoxin antagonist BPI21 showed improved gastric mucosal lesion, accompanied by the declining TNF-α level. Conclusions Our results suggestes that endotoxin may play a pathogenetic role in PHG by inducing the expression of TNF-α.

Irsogladine, an anti-ulcer drug, suppresses superoxide production by inhibiting phosphodiesterase type 4 in human neutrophils

Neutrophil superoxide production is implicated in the pathogenesis of gastric mucosal damage induced by various ulcerative agents and Helicobacter pylori infection. We investigated here the effects of an anti-ulcer drug irsogladine [2, 4-diamino-6-(2, 5-dichlorophenyl)-s-triazine maleate] on cAMP formation in isolated human neutrophils. The cAMP level in human neutrophils was elevated by a phosphodiesterase (PDE) type 4 selective inhibitor rolipram, but not by any inhibitors of PDE1, PDE2 and PDE3. Irsogladine also increased cAMP formation in a concentration-dependent manner in neutrophils. A non-selective PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX) alone significantly increased cAMP level, whereas irsogladine was unable to further increase cAMP level in the presence of IBMX. Irsogladine inhibited concentration-dependently the superoxide (O2−) production induced by various stimuli including formyl-methionyl-leucyl-phenylalanine, opsonized zymosan, guanosine 5′-[gamma-thio] triphosphate, A23187 and phorbol 12-myristate 13-acetate. These effects of irsogladine were mimicked by rolipram, IBMX and dibutyryl cAMP. The inhibitory effects of irsogladine and rolipram on the O2− production were reversed by a protein kinase A inhibitor H-89. These results indicate that irsogladine inhibits the superoxide production in human neutrophils by the increase of cAMP content by PDE 4 inhibition, which in turn contributing to the anti-ulcer effects of irsogladine on gastric mucosal lesions associated with oxidative stress.

Effect of Helicobacter pylori-mediated inflammation on nonsteroidal anti-inflammatory drugs-induced gastric mucosal injury.

Helicobacter pylori (H. pylori) infection and nonsteroidal anti-inflammatory drugs (NSAIDs) are two major causes of gastric ulceration, but relation between H. pylori infection and use of these drugs in gastric mucosal injury is controversial. Neutrophils have been implicated in the pathogenesis of gastric mucosal damage induced by H. pylori or NSAIDs. H. pylori itself and H. pylori extract induce neutrophil activation, such as superoxide production, expression of adhesion molecule (CD11b/CD18) and transendothelial migration, capillary plugging. Several clinical and experimental studies demonstrated that the degree of H. pylori-induced gastric mucosal injury was closely correlated with the extents of H. pylori infection and of neutrophil infiltration, suggesting implication in extravascular neutrophils for H. pylori-induced gastric mucosal injury. On the other hand, aspirin promotes neutrophil-endothelial adhesive interactions via increasing CD11b/CD18, but not neutrophil migration to extravascular space. In addition, our recent in vivo study suggests that neutrophils adhering to the blood vessels, but not neutrophils migrating to the interstitium, are implicated in aspirin-induced gastric mucosal injury. Recently, we found that administration of aspirin to gerbils three weeks after H. pylori inoculation produced severe gastric mucosal injury via marked infiltration of neutrophils. In this animal model, pretreatment with anti-neutrophil serum, elastase inhibitor or scavengers of reactive oxygen species remarkably inhibited gastric mucosal injury. These results suggest that H. pylori infection potentiates aspirin-induced gastric mucosal injury by mechanisms that include accumulation of activated neutrophils.

Mechanisms underlying gastric antiulcerative activity of nitroxides in rats

Reactive oxygen-derived species and redox-active metals are implicated in mediation of the pathogenesis of gastric mucosal damage and ulceration. Therefore, common strategies of intervention employ metal chelators, antioxidative enzymes, and low-molecular-weight antioxidants (LMWA). The aim of the present study was to elaborate the mechanism(s) responsible for the protection provided by nitroxide radicals in the experimental model of gastric ulceration.Fasted male rats were treated ig with 1 ml 96% ethanol, with or without ig pretreatment with nitroxide or hydroxylamine. In several experiments, rats were injected ip or iv with iron(III) or iron(II) prior to ethanol administration. Rats were sacrificed 10 min after ethanol administration, the stomach was removed, washed and lesion area measured. Pretreatment with iron(III) complexed to nitrilotriacetate or citrate, aggravated the extent of the gastric injury. Conversely, iron(III) inhibited the formation of lesions. The nitroxides were rapidly reduced to their respective hydroxylamines and demonstrated antiulcerative activity for rats treated with iron. However, injecting the hydroxylamine resulted in a similar tissue distribution of nitroxide/hydroxylamine but did not provide protection.The results show that: (a) the nitroxide radicals, rather than their respective non-radical reduced form, are the active species responsible for protection; (b) nitroxides protect by dismutating O·-2 and possibly indirectly increasing the NO level; (c) unlike classical LMWA which are reducing agents, nitroxides inhibit gastric damage by acting as mild oxidants, oxidizing reduced metals and pre-empting the Fenton reaction; and (d) the nitroxides act catalytically as recycling antioxidants.

Role of nitric oxide in pathogenesis of gastric mucosal damage induced by compound [formula omitted] in rats

We examined the effects of various nitric oxide synthase (NOS) inhibitors on development of gastric lesions induced by compound 48 80 ( 48 80 ) in rats and investigated the roles of NO and inducible NOS (iNOS) in inflammatory gastric responses. Animals were given 48 80 (1 mg/kg, ip) once daily for 4 days, and the stomachs were examined for lesions 24 h after the final administration. NOS inhbitors such as L-NAME, L-NMMA, aminoguanidine or dexamethasone were administered for 4 days during 48 80 treatment. The repeated administration of 48 80 caused damage in the stomach with severe edema in the submucosa. These lesions induced by 48 80 were dose-dependently prevented by concurrent administration of L-NAME. The protective effect of L-NAME on 48 80 - induced gastric lesions was mimicked by L-NMMA, aminoguanidine as well as dexamethasone, and significantly antagonized by co-administration of L-arginine but not by D-arginine. Acid secretion was slightly decreased after 48 80 treatment, but was significantly augmented by the combined administration of L-NAME with 48 80 . The mucosal MPO activity, TBA reactants and vascular permeability in the stomach were all increased after 48 80 treatment, but these changes were also significantly mitigated by co-administration of L-NAME. The Ca 2+-independent NOS activity in the mucosa was increased four times during 48 80 treatment, and this change was also inhibited by dexamethasone. These results suggest that: 1) the repeated administration of 48 80 induced inflammatory gastric lesions in the rat stomach; 2) the pathogenic mechanism of these lesions involves endogenous NO produced by iNOS, in addition to oxyradical formation; and 3) the deleterious role of NO during 48 80 treatment may be accounted for by a cytotoxic action of peroxynitrite, which is formed in the presence of NO and superoxide radicals.

Bosentan, a novel synthetic mixed-type endothelin receptor antagonist, attenuates acute gastric mucosal lesions induced by indomethacin and HCl in the rat: role of endogenous endothelin-1.

Endothelin-1 has been reported to be responsible for gastric mucosal damage in various experimental models. We evaluated the role of endogenous endothelin-1 in the pathogenesis of gastric mucosal damage induced by indomethacin and HCl in the rat. Rats were given indomethacin (25 mg/kg) subcutaneously, and 15 min later, 0.2N HCl intragastrically. Gastric mucosal damage, gastric endogenous endothelin-1, and gastric mucosal hemodynamics were measured. The effects of bosentan, a mixed endothelin receptor antagonist, on gastric mucosal integrity and hemodynamics were assessed. Gastric endogenous endothelin-1 was significantly elevated at 20 min, gastric mucosal blood flow began to decrease significantly at 25 min, and gastric damage occupied 52.2% of the total glandular mucosa at 135 min after injection of indomethacin. Intragastric pretreatment with bosentan (5, 10, 30, and 60 mg/kg) significantly attenuated gastric damage, to 26.1%, 7.7%, 3.6%, and 1.6%, respectively, of the total glandular mucosa. Bosentan (60 mg/kg) prevented the initial decrease of blood flow and, even at 135 min, improved blood flow and hemoglobin oxygen saturation significantly. We suggest that indomethacin-induced endogenous endothelin-1 diminishes gastric mucosal blood flow and tissue oxygenation and ultimately causes gastric damage. Endogenous endothelin-1 may play an important role in the pathogenesis of the acute gastric mucosal lesions induced by indomethacin and HCl.

Cytokine effects on pepsinogen secretion from human peptic cells.

Different cytokines, including epidermal growth factor (EGF) and interleukin 1 beta (IL 1 beta), participate in the pathogenesis of gastric mucosal damage and repair by means of different mechanisms that are either paracrine or autocrine in nature. To study whether EGF and IL 1 beta affect pepsinogen secretion in vitro. Dispersed human peptic cells were prepared from endoscopically obtained biopsy specimens after collagenase digestion, mechanical disruption, and density gradient centrifugation. EGF dose dependently increased basal pepsinogen secretion and mitogenic concentrations (0.1 nM) of EGF induced submaximal stimulation. Similar effects were observed with transforming growth factor alpha. EGF effects on pepsinogen secretion were in addition to that induced by CCK-OP and db-cAMP stimulated pepsinogen secretion. EGF stimulated pepsinogen secretion was completely inhibited by a human immunospecific EGF receptor antibody and reduced by both genistein and tyrphostin-25, two different tyrosine kinase inhibitors. IL 1 beta does not affect basal, CCK-OP or acetylcholine stimulated pepsinogen secretion. However, IL 1 beta dose dependently inhibited db-cAMP and histamine stimulated pepsinogen secretion. These results show that both EGF and IL 1 beta modulate human pepsinogen secretion in vitro and suggest that the paracrine effects of these cytokines on pepsinogen secretion might be involved in some pathological conditions of damage and inflammation of the gastric mucosa.

Role of endothelin-1 in repeated electrical stimulation-induced microcirculatory disturbance and mucosal damage in rat stomach.

The aim of the present study was to clarify the involvement of endogenous endothelin in the pathogenesis of gastric mucosal damage. The rat stomach was exposed and repeated electrical stimulation (RES) was applied to the small arterial wall close to the lesser curvature. Significant mucosal haemorrhagic lesions (ulcer and erosion) were noted within 30 min after RES. Intravital microscopic observations revealed that an arteriolar constriction occurred in the submucosal layer of the rat stomach approximately 5 min after the completion of RES. Following the arteriolar constriction, the mucosal blood flow of the rat stomach, which was monitored by using a laser Doppler velocimeter, decreased to approximately 30% of the control value. The plasma immunoreactive endothelin-1 level in the regional blood of the stomach was significantly increased immediately after RES preceding the decrease in mucosal blood flow. Immunohistochemical studies revealed that endothelin-1 and big-endothelin-1 were detectable in the arteriolar endothelium around the muscularis mucosa, supporting the involvement of endothelin-1 in RES-induced mucosal ischaemia. In addition, BQ-123, a specific antagonist of the endothelin A (ETA) receptor, attenuated the reduction of blood flow and the development of haemorrhagic lesions observed in gastric mucosa subjected to RES. The results of the present study suggest that an excessive production of endothelin-1 in the arteriolar endothelium leads to microvascular derangements accompanied by haemorrhagic alterations of the gastric mucosa.

Effects of 16, 16-dimethyl prostaglandin E2 on lysosomal membrane stability in rat stomach

The lysosomal membrane encloses numerous hydrolytic enzymes and prevents the cytoplasm from being damaged by these enzymes. It is possible that the fragility of this membrane may be implicated in the pathogenesis of gastric mucosal damage. We investigated the effects of 16,16-dimethyl prostaglandin E2 (dmPGE2), which is known to protect the gastric mucosa from various noxious agents, on lysosomal membrane stability in the rat stomach. Sodium taurocholate (TC) was used as the damaging agent. To assess lysosomal membrane stability in the gastric mucosa, we assayed acid phosphatase released from lysosomes isolated from a gastric mucosal homogenate. To assess lysosomal membrane stability in gastric surface epithelial cells, we used laser scanning confocal microscopy to observe the fading of red fluorescence in living cells vitally stained with acridine orange. Exogenous dmPGE2 enhanced lysosomal membrane stability in the gastric mucosa, whereas TC decreased it. In gastric surface epithelial cells, exogenous dmPGE2 protected the cells against TC-induced damage and prevented TC-induced decreased lysosomal membrane stability. It was concluded that a decrease in lysosomal membrane stability seemed to be closely involved in the pathogenesis of gastric mucosal damage. Moreover, it appears that stabilization of the lysosomal membrane by exogenous dmPGE2 may contribute to its protective effect in the gastric mucosa, both at the level of gastric surface epithelial cells and in regard to the entire gastric mucosa.

Role of platelet activating factor on the fibrinolytic activation in the pathogenesis of gastric mucosal damage induced by endothelin-1.

We have examined the hypothesis that the release of tissue type plasminogen activator may play a prominent role in endothelin induced gastric mucosal injury. We determined tissue type plasminogen activator activity in the regional blood sample and the concentration of platelet activating factor in the gastric mucosa after the administration of endothelin-1 in a range of 50-500 pmol/kg into the left gastric artery of male Wistar rats. Endothelin-1 increased the tissue type plasminogen activator release and platelet activating factor formation, and induced subsequent gastric mucosal haemorrhagic change in a dose dependent manner. In addition CV-6209, a selective platelet activating factor blocker, attenuated the activation of regional tissue type plasminogen activator and the development of mucosal damage induced by endothelin-1. The results of this study showed that tissue type plasminogen activator activation may play an important role in the pathogenesis of endothelin induced mucosal injury of rat stomach, and suggest that the platelet activating factor may be involved in the process of regional fibrinolytic activation induced by endothelin-1.

Pathogenesis of gastric mucosal damage induced by intraperitoneal administration of gold thioglucose in rats

Rats injected intraperitoneally with gold thioglucose (GTG,0.3mg/g) revealed hemorrhagic lesions in the gastric mucosa 24h after the injection. However, no morphological changes were found in the central nervous system after the injection. The volume of gastric secretion and acid output increased significantly 24h after the injection (P less than 0.01), and gastric emptying was markedly inhibited 24h post administration (P less than 0.01). There were no changes in either blood flow or hexosamine contents in the gastric mucosa. These results indicated that gastric hemorrhagic lesion was associated with increases in gastric secretion and acid output. No significant changes were found in gastrin contents in either plasma or the gastric mucosa. A subdiaphragmatic vagotomy prior to the GTG injection prevented bleeding in the gastric mucosa and lowered the gastric secretion and acid output. This indicated that the mechanism of action of GTG in producing the gastric lesion might be mediated by the vagus nerve.

Effect of Plasmin Inhibitors on Gastric Mucosal Permeability in Rats

We examined the protective effect of plasmin inhibitors on gastric mucosal vascular permeability in rats. Tranexamic acid and aminocaproic acid significantly inhibited the increase in vascular permeability and macroscopic gastric mucosal lesions induced by 50% ethanol and 1% ammonia. The protective effect afforded by plasmin inhibitors was not affected by pretreatment with indomethacin. Our results show that plasmin inhibitors inhibit the increase in gastric vascular permeability and suggest that plasmin may play an important role in the pathogenesis of gastric mucosal damage.

Gastric cytoprotection: a critical appraisal of the concept, methodology, implications, mechanisms and future research prospects.

Gastric cytoprotection is the property of certain substances, particularly prostaglandins, when used in non-antisecretory doses, to protect the gastric mucosa from becoming inflamed and necrotic on being exposed to noxious agents. An association between alterations in endogenous prostaglandins and gastric mucosal damage induced by a number of drugs has also been observed. The process of adaptive cytoprotection in which mild irritants protect the gastric mucosa against the damaging effects of various necrotizing agents has been shown to be prostaglandin mediated. However, the exact mechanisms underlying this cytoprotective activity have still not been elucidated although a number of hypotheses have been proposed. Recently, thromboxanes, leukotrienes and endogenous sulfhydryls have also been suggested to be involved in the pathogenesis of gastric mucosal damage induced by various necrotizing agents. This review attempts to provide an up-to-date appraisal of the concept, methodology, mechanisms and implications of this phenomenon and suggests that prostaglandins and endogenous sulfhydryls may play a significant role in the pathogenesis of gastric ulceration and may serve an important function in maintaining normal gastric mucosal integrity.

Studies of Acid and Alkaline Secretion by Rabbit Gastric Fundus In Vitro: Effect of Low Concentrations of Sodium Taurocholate

The effect of low concentrations of sodium taurocholate on the secretory and electrical activity of isolated rabbit fundic mucosa has been studied. Fundic mucosa maintained a stable potential difference (10.2 +/- 0.6 mV, n = 70) and electrical resistance (85 +/- 6 omega . cm-2, n = 70) and the majority of preparations spontaneously secreted acid (2.85 +/- 0.31 mumol . cm-2 . h-1, n = 70). Histamine (10(-5) and 10(-4) M) and carbachol (10-4 M) increased acid secretion, and these responses were prevented by cimetidine (10(-3) M) and atropine (10(-5) M), respectively. Mucosal application of taurocholate (10(-4) and 10(-3) M) increased net acidity without altering electrical activity. This response exhibited tachyphylaxis, was not altered by pretreating the tissues with cimetidine (10(-3) M), atropine (10(-5) M), or somatostatin (10(-6) M), and occurred in mucosas maximally stimulated by histamine. Sodium thiocyanate (6 x 10(-2) M, serosal side) inhibited spontaneous acid secretion revealing net alkalinization (0.83 +/- 0.05 mumol . cm-2 . h-1, n = 58) that was completely inhibited by anoxia and potassium cyanide (10(-2) M) and markedly reduced by 2,4-dinitrophenol (10(-4) M). Some fundic preparations spontaneously secreted alkali (1.20 +/- 0.20 mumol . cm-2 . h-1, n = 6) after an initial period of acid secretion. Mucosal-side taurocholate (10(-3) M) converted net alkali secretion by both thiocyanate-treated and spontaneously-secreting mucosas to acid secretion without affecting electrical conductance. These secretory responses may be implicated in the pathogenesis of gastric mucosal damage by bile salts.