Formation Of Gastric Mucosal Lesions Research Articles

The apelin-apela receptor APJ is necessary for formation and healing of ischemia reperfusion-induced gastric ulcer in rats

The apelinergic system widely expressed and regulates hormone-enzyme secretion, motility, and protective mechanisms of the stomach. This system consists of the apelin receptor (APJ) and two peptides known as apela and apelin. The IR-induced experimental gastric ulcer model is a well-known and commonly used one that induces hypoxia and causes the release of proinflammatory cytokines. Expressions of apelin and its receptor APJ are induced by hypoxia and inflammation in the gastrointestinal tract. Apelin has been shown to affect angiogenesis positively, considered the most critical component of the healing process. Although it is known that apelin and AJP expressions are induced by inflammatory stimuli and hypoxia, stimulate endothelial cell proliferation and have a role in regenerative angiogenesis, no information or has been found in the literature regarding the role of APJ in the formation and healing of gastric mucosal lesions induced by I/R. So, we conducted a study to clarify the role of APJ in formation and healing mechanisms of IR-induced gastric lesions. Male Wistar rats were divided into five groups; control, sham-operated, IR, APJ antagonist treated-IR group (F13A+IR), and the healing groups. F13A was intravenously given to the animals. Gastric lesion index, mucosal blood flow, PGE2, NOx, 4-HNE-MDA, HO activity, and protein expressions of VEGF and HO-1 were measured. F13A application before the IR increased the mucosal injury, F13A application following the ischemia delayed the mucosal healing during the reperfusion period. Consequently, blocking apelin receptors may worsen gastric injury due to the IR and delay mucosal healing.

Pretreatment with Lactobacillus fermentum XY18 Relieves Gastric Injury Induced by HCl/Ethanol in Mice via Antioxidant and Anti-Inflammatory Mechanisms.

AimLactobacillus fermentum XY18 (LF-XY18) is a bacterial strain with satisfactory antioxidant properties in vitro that we previously isolated from Xinjiang yogurt. This article will explore the preventive effect of LF-XY18 on acute gastric injury and provide the basis for the innovative development and application of lactic acid bacteria (LAB).MethodsKunming mice underwent gastric injury induced by hydrochloric acid and ethanol. LF-XY18 isolated from yogurt in Xinyuan County in the Yili region of Xinjiang was subsequently administered intragastrically to mice for 2 weeks to explore the mechanism of LF-XY18 in preventing gastric injury via its antioxidant effects.ResultsThere was decreased gastric juice volume, gastric injury area, and formation of gastric mucosal lesions in the LF-XY18 mice as compared to those in the control mice, while LF-XY18 prevented the decrease in the gastric juice pH value in mice. Compared with the gastric injury model group mice, LF-XY18 reduced the serum levels of motilin, substance P, interleukin-6, interleukin-12, tumor necrosis factor-α, and interferon-γ but increased the serum levels of somatostatin and vasoactive intestinal peptide. The activities of superoxide dismutase, glutathione peroxidase, glutathione, and nitric oxide were increased in the gastric tissue of the LF-XY18 mice compared with the control mice, but malondialdehyde activity was decreased in the LF-XY18 mice. Quantitative polymerase chain reaction analysis illustrated that in the gastric tissue of LF-XY18 mice, the messenger RNA (mRNA) expression of occludin, epidermal growth factor (EGF), EGF receptor, vascular EGF, inhibitor kappa-B-α, neuronal nitric oxide synthase, endothelial nitric oxide synthase, cuprozinc superoxide dismutase, manganese superoxide dismutase, and catalase was stronger than that in the control mice, but the mRNA expression of activated B cells (NF-κB), inducible nitric oxide synthase, and cyclooxygenase-2 was weaker than in the control mice.ConclusionThese results indicate that LF-XY18 has a potential role in the prevention of gastric injury through antioxidant effects, and a high concentration (1.0 × 109 CFU/kg b.w.) of LF-XY18 has a stronger anti-gastric injury effect than a low concentration (1.0 × 108 CFU/kg b.w.).

Role of Cannabinoids in Gastrointestinal Mucosal Defense and Inflammation.

Modulating the activity of the endocannabinoid system influences various gastrointestinal physiological and pathophysiological processes, and cannabinoid receptors as well as regulatory enzymes responsible for the synthesis or degradation of endocannabinoids representing potential targets to reduce the development of gastrointestinal mucosal lesions, hemorrhage and inflammation. Direct activation of CB1 receptors by plant-derived, endogenous or synthetic cannabinoids effectively reduces both gastric acid secretion and gastric motor activity, and decreases the formation of gastric mucosal lesions induced by stress, pylorus ligation, nonsteroidal anti-inflammatory drugs (NSAIDs) or alcohol, partly by peripheral, partly by central mechanisms. Similarly, indirect activation of cannabinoid receptors through elevation of endocannabinoid levels by globally acting or peripherally restricted inhibitors of their metabolizing enzymes (FAAH, MAGL) or by inhibitors of their cellular uptake reduces the gastric mucosal lesions induced by NSAIDs in a CB1 receptor-dependent fashion. Dual inhibition of FAAH and cyclooxygenase enzymes induces protection against both NSAID-induced gastrointestinal damage and intestinal inflammation. Moreover, in intestinal inflammation direct or indirect activation of CB1 and CB2 receptors exerts also multiple beneficial effects. Namely, activation of both CB receptors was shown to ameliorate intestinal inflammation in various murine colitis models, to decrease visceral hypersensitivity and abdominal pain, as well as to reduce colitis-associated hypermotility and diarrhea. In addition, CB1 receptors suppress secretory processes and also modulate intestinal epithelial barrier functions. Thus, experimental data suggest that the endocannabinoid system represents a promising target in the treatment of inflammatory bowel diseases, and this assumption is also confirmed by preliminary clinical studies.

Gastroprotective Effect of Selenium on Ethanol-Induced Gastric Damage in Rats

In the present study, we examined the gastroprotective effect of selenium against ethanol-induced gastric mucosal lesions in rats. The gastric mucosal lesions were produced by oral administration with various concentrations of ethanol for three days, and 80% ethanol treatment was determined to be the optimal condition for induction of gastric damage. To identify the protective effect of selenium on ethanol-induced gastric damage, various doses of selenium were given as pretreatment for three days, and then gastric damage was induced by 80% ethanol treatment. Selenium showed a protective effect against ethanol-induced gastric mucosal lesions in a dose dependent manner. Specifically, 100 μg/kg selenium showed the highest level of gastroprotection. In addition, selenium markedly attenuated ethanol-induced lipid peroxidation in gastric mucosa and increased activities of radical scavenging enzymes, such as superoxide dismutase (SOD), catalase, and glutathione peroxidase in a dose-dependent manner. Histological data showed that 100 μg/kg selenium distinctly reduced the depth and severity of the ethanol induced gastric lesion. These results clearly demonstrate that selenium inhibits the formation of ethanol-induced gastric mucosal lesions through prevention of lipid peroxidation and activation of enzymatic radical scavenging.

Role of polymorphonuclear leucocytes and oxygen-derived free radicals in the formation of gastric lesions induced by HCl/ethanol, and a possible mechanism of protection by anti-ulcer polysaccharide.

This study examined the role of oxygen-derived free radicals in the pathogenesis of gastric mucosal lesions induced by HCl/ethanol. Superoxide dismutase, and catalase, and their combination reduced gastric lesion formation in mice. Gastric lesions were also reduced in mice treated with cyclophosphamide or anti-neutrophils, but not in mice treated with allopurinol or desulphated-carrageenan. Cobra venom factor did not reduce lesion formation. These results suggested that oxygen-free radicals may contribute to the formation of gastric mucosal lesions induced by HCl/ethanol, and that oxygen radicals were generated from neutrophils but not from xanthine oxidase. Anti-ulcer pectic polysaccharide, bupleuran 2IIc, which was recently isolated from the roots of Bupleurum falcatum L., showed potent inhibition of HCl/ethanol-induced gastric lesions in mice. Bupleuran 2IIc seemed to scavenge hydroxyl radical effectively. It was suggested that this anti-ulcer polysaccharide may provide protection to the gastric mucosa by scavenging oxygen-free radicals.

Isoliquiritigenin Selectively Inhibits H2Histamine Receptor Signaling

Isoliquiritigenin, one of the major constituents of Glycyrrhiza uralensis (licorice), is a natural pigment with a simple chalcone structure 4,2',4'-trihydroxychalcone. In this study, isoliquiritigenin showed selective H(2) histamine receptor (H(2)R) antagonistic effect and remarkably reduced several H(2)R-mediated physiological responses. Preincubation of U937 and HL60 hematopoietic cells with isoliquiritigenin significantly inhibited H(2)R agonist-induced cAMP response in a concentration-dependent manner without affecting the viability of cells. Isoliquiritigenin also blocked the binding affinity of [(3)H]tiotidine to membrane receptors in HL-60 cells. Isoliquiritigenin did not affect the elevation of cAMP levels induced by cholera toxin, forskolin, or isoproterenol, indicating that the action site of isoliquiritigenin is not G(s) protein, effector enzyme, adenylyl cyclase, or beta(2)-adrenoceptor. Isoliquiritigenin affected neither H(1)R-nor H(3)R-mediated signaling. In molecular docking studies, isoliquiritigenin exhibited more favorable interactions with H(2)R than histamine. Isoliquiritigenin prominently inhibited H(2)R selective agonist dimaprit-induced cAMP generation in MKN-45 gastric cancer cell. Moreover, isoliquiritigenin reduced gastric acid secretion and protected gastric mucosal lesion formation in pylorus-ligated rat model. Taken together, the results demonstrate that isoliquiritigenin is an effective H(2)R antagonist and provides the basis for designing novel H(2)R antagonist.

Preventive and curative effects of curcumin on the development of gastric inflammatory diseases in rats.

Preventive and curative effects of curcumin on experimental acute and chronic gastric ulcers were investigated to validate its clinical application on a remedy for peptic ulcer. Intraduodenal administration of curcumin, 5-20mg/kg, inhibited gastric acid secretion in pylorus-ligated rats, and oral administration prevented ethanol-induced acute gastric mucosal lesions. Curcumin (20-80mg/kg, p.o.) dose-dependently prevented both serotonin-induced gastric mucosal lesions and compound 48/80-induced gastric mucosal lesions in rats. Furthermore, oral administration of curcumin, 10-80mg/kg, twice daily for 10days, significantly accelerated the healing of acetic acid-induced chronic gastric ulcer and promoted mucosal regeneration in the ulcerated portion in a dose-related manner. Cimetidine prevented the formation of ethanol-induced gastric mucosal lesions, but not of serotonin-induced and compound 48/80-induced gastric mucosal lesions. Consecutive administration of cimetidine showed a marked acceleration in the healing of acetic acid-induced ulcer. Aminoguanidine, an inducible nitric oxide synthase (iNOS) inhibitor, showed anti-ulcerogenic effects similar to those oberved for curcumin. The present results indicate that curcumin exhibits gastric cytoprotection in the acute lesion models and ulcer healing promotion in the chronic ulcer model. The preventive and curative effects of curcumin might be due to an increase in the mucosal defensive mechanism through its antioxidant property and inhibition of NO or cytokine-mediated inflammation.

Oxidative Stress In Helicobacter pylori-Assocaited Gastroduodenal Disease

Helicobacter pylori (H. pylori) is a spiral-shaped, Gram-negative rod, which induces the infiltration to the gastric mucosa by neutrophils, macrophages, and T and B lymphocytes; however, this immune and inflammatory response cannot completely clear the bacterial infection, and leaves the host prone to complications resulting from persistent inflammation. Resultantly, H. pylori infection causes chronic inflammation, accumulation of reactive oxygen species, and oxidative DNA damage in the gastric mucosa. Recent studies reveal that H. pylori injects bacterial proteins into the cytosol of the gastric host cell via the type IV injection system and regulates the intracellular signal transduction [1, 2]. This mechanism provides a novel means of resolving how H. pylori survives in the acidic environment of the human stomach. During persistent gastric infections, chronic gastritis may remain asymptomatic or may evolve into more severe diseases, such as peptic ulcer disease or atrophic gastritis. In addition, infection with H. pylori increases the risk of developing gastric cancer and mucosa-associated lymphoid tissue lymphoma. Various gastric diseases, such as gastritis, ulcers, intestinal metaplasia, and gastric cancer, can be appropriately developed by inoculating this bacteria into Mongolian gerbils [3]. In addition, the successful eradication of H. pylori is useful as a preventive approach against gastric cancer [4]. This review focuses on the aspects of the oxidative mechanism in the H. pylori-associated gastric mucosal lesion formation.

Curcuma longa Extract Protects against Gastric Ulcers by Blocking H2 Histamine Receptors

Curcuma longa has been commonly used as a traditional remedy for a variety of symptoms such as inflammation, gastritis and gastric ulcer. When C. longa extract was administered per os to pylori-ligated rat stomachs, it reduced gastric acid secretion and protected against the formation of gastric mucosal lesions. We therefore tested whether C. longa extract inhibits gastric ulcers by blocking the H(2) histamine receptor. Dimaprit, a H(2) histamine receptor agonist, induced intracellular cAMP production in U937 and HL-60 promyelocytes. Pretreatment with C. longa extract significantly blocked dimaprit-induced cAMP production in a concentration dependent manner, but had no effect on the elevation of cAMP levels triggered by isoproterenol-induced beta(2)-adrenoceptor activation in U937 cells. To identify the active component(s) of C. longa extract, we sequentially fractionated it by extraction with ethyl acetate, n-butanol and water. We found that the ethyl acetate extract showed the most potent H(2)R antagonistic effect against dimaprit-induced cAMP production. However, curcumin, a major component of C. longa extract, showed no H(2)R blocking effect. C. longa ethanol extract and ethylacetate extract also blocked the binding of [(3)H]-tiotidine to membrane receptors on HL-60 cells. These findings suggest that the extract from C. longa specifically inhibits gastric acid secretion by blocking H(2) histamine receptors in a competitive manner.

A Change in Gastric Mucosal Ascorbic Acid Status with the Formation, Progression, and Recovery of Compound 48/80-induced Acute Gastric Mucosal Lesions in Rats

We examined whether gastric mucosal ascorbic acid status changes with the formation, progression, and recovery of acute gastric mucosal lesions in rats treated with compound 48/80, a mast cell degranulator. Fasted Wistar rats received a single intraperitoneal injection of compound 48/80 (0.75 mg/kg). Apparent gastric mucosal lesions occurred 0.5 h after compound 48/80 treatment, progressed gastric mucosal lesions were observed at 3 h, and a partial recovery of the progressed lesions was found at 6 h. The gastric mucosal concentrations of total and reduced ascorbic acids in compound 48/80-treated rats decreased to approximately 60% of the levels of untreated rats at 3 h after the treatment but the decreased concentrations of total and reduced ascorbic acids were almost completely returned to the levels of untreated rats at 6 h. The gastric mucosal concentration of oxidized ascorbic acid in compound 48/80-treated rats showed little change. The serum concentrations of total and reduced ascorbic acids in compound 48/80-treated rats increased at 0.5 h after the treatment and further increased at 3 h but the increased concentrations of total and reduced ascorbic acids were almost completely returned to the levels of untreated rats at 6 h. The serum concentration of oxidized ascorbic acid in compound 48/80-treated rats increased transiently at 0.5 h after the treatment. The hepatic concentrations of total. reduced, and oxidized ascorbic acids in compound 48/80-treated rats increased 3 h after the treatment, but these increases were not observed at 6 h. These results indicate that gastric mucosal ascorbic acid status is disrupted with the progression of acute gastric mucosal lesions in rats treated with compound 48/80.

Protective effect of coadministered superoxide dismutase and catalase against stress-induced gastric mucosal lesions.

1. There are conflicting reports as to the protective effect of coadministered native superoxide dismutase (SOD) and catalase against gastric mucosal lesions in rats with water immersion restraint (WIR) stress. It is unclear how coadministered native SOD and catalase protect against WIR stress-induced gastric mucosal lesions. Therefore, in the present study, we re-examined the protective effect of coadministered native SOD and catalase against gastric mucosal lesions in rats with WIR stress. 2. Gastric mucosal lesions were induced in Wistar rats by 3 h WIR. Rats were injected subcutaneously with a mixture of purified bovine erythrocyte SOD and bovine liver catalase 1 h before the onset of WIR. Ulcer index, serum SOD, catalase and xanthine oxidase (XO), uric acid and gastric mucosal SOD, catalase, XO, myeloperoxidase (MPO; an index of tissue neutrophil infiltration), non-protein sulfhydryl (NP-SH) and thiobarbituric acid-reactive substances (TBARS; an index of lipid peroxidation) were assayed in all rats used. 3. Rats with 3 h WIR showed gastric mucosal lesions. Pre-administration of SOD plus catalase to rats with WIR prevented lesion formation. In the serum of rats with WIR alone, XO activity and uric acid concentration increased, whereas SOD and catalase activities did not change. Pre-administration of SOD plus catalase to rats with WIR did not affect increased serum XO activity and uric acid concentration, but did increase serum SOD and catalase activities. In the gastric mucosa of rats with WIR alone, increases in MPO activity and TBARS concentration and a decrease in NP-SH concentration occurred, whereas XO, SOD and catalase activities did not change. Pre-administration of SOD plus catalase to rats with WIR attenuated the changes in gastric mucosal MPO activity and TBARS and NP-SH concentrations, but did not affect gastric mucosal XO, SOD and catalase activities. Pre-administration of SOD plus catalase (in an inactivated form) to rats with WIR had no effect on gastric mucosal lesion formation and the levels of serum and gastric mucosal parameters studied. 4. These results indicate that coadministered native SOD and catalase protect against gastric mucosal lesions in rats with WIR stress and suggest that this protective effect of coadministered native SOD and catalase could be due to their activity to scavenge XO-derived active oxygen species that are increased in the blood.

Rabeprazole treatment attenuated Helicobacter pylori-associated gastric mucosal lesion formation in Mongolian gerbils.

Although rabeprazole (RPZ), a proton pump inhibitor, has been reported to have a bactericidal effect on Helicobacter pylori (H. pylori), no studies have been conducted regarding the effect of RPZ on gastric mucosal lesion formation caused by this bacterium. In the present study, we investigated the effect of RPZ on H. pylori-associated gastric mucosal lesion formation. Sixty-two male Mongolian gerbils were inoculated with H. pylori (ATCC43504) (Hp group) and 60 gerbils with the culture media alone (control group). Some gerbils in the Hp group and in the control group were injected with RPZ (1 mg/kg/day, for 7 days) at the 5th week. Gerbils were evaluated at the 12th, 24th and 48th weeks. In the Hp group, all gerbils were persistently infected for 24 weeks, but 36% became negative for H. pylori at the 48th week. In the Hp + RPZ group, 18% of gerbils at the 12th week, 40% at the 24th week, and 80% at the 48th week, became negative for H. pylori. The level of neutrophil infiltration was significantly decreased in the Hp + RPZ group in comparison to the Hp group, possibly through the effects of RPZ on initial bacterial colonization and resultant inflammation. Even in the gerbils that became H. pylori-negative, the level of neutrophil infiltration was lower in the Hp + RPZ group than in the Hp group. RPZ treatment significantly increased the level of the reduced form of glutathione (GSH) at the 48th week. The elevated levels of the reduced form of GSH may have been reduced by an antioxidation process in the H. pylori-positive Hp + RPZ group. Administration of RPZ not only inhibited gastric H. pylori colonization, but also reduced gastric mucosal inflammation in gerbils, possibly through its antibacterial action as well as pharmacological recruitment of the reduced form of GSH.

Abamectin attenuates gastric mucosal damage induced by ethanol through activation of vagus nerve in rats

Some type A gamma-aminobutyric acid (GABA A) receptor agonists are effective in protecting against the formation of stomach lesions induced by ethanol. Natural product abamectin, one of the existing GABA A receptor agonists, might protect against the development of gastric ulcers induced by ethanol. We investigated the protective effect of abamectin against the formation of gastric mucosal lesions induced by ethanol in rats. Abamectin (3 mg/kg, p.o.) was given to rats 1 h before administration of ethanol [4 ml of a 30% (volume/volume) solution]. Mucosal lipid peroxidation (LPO), nitric oxide (NO) levels, and ulcer index were measured 3 h after gastric surgery (vagotomy vs. sham vagotomy) in treated versus control subjects. Abamectin attenuated ethanol-induced gastric ulceration, decreased LPO regeneration, and increased NO production in the gastric mucosa of rats in the sham vagotomy group. However, this protective effect of abamectin against ethanol-induced gastric lesions was not observed in rats in the group that underwent vagotomy. These results support the suggestion that administration of abamectin ameliorated the ethanol-induced gastric mucosal injury through elevation of NO production. Activation of the vagus nerve may be involved in the abamectin-associated gastric protection against the effects of ethanol in rats.

Irsogladine Prevents Monochloramine-Induced Gastric Mucosal Lesions by Improving the Decrease in Mucosal Blood Flow Due to the Disturbance of Nitric Oxide Synthesis in Rats

The inhibitory effect of an anti-ulcer drug irsogladine [2,4-diamino-6-(2,5-dichlorophenyl)-s-triazine maleate] on monochloramine (NH(2)Cl)-induced gastric mucosal lesions and its mechanisms of action were clarified in rats. Irsogladine dose-dependently prevented the formation of gastric mucosal lesions induced by 60 mM NH(2)Cl. The mucosal protective effect of irsogladine was not influenced by capsaicin-sensitive sensory defunctionalization. On the other hand, its protective effect was diminished by the inhibitor of nitric oxide synthase N(G)-nitro-L-arginine methylester (L-NAME), but not by the inducible nitric oxide synthase selective inhibitor aminoguanidine. Irsogladine restored the NH(2)Cl-induced decrease in the gastric cGMP formation as an index of nitric oxide synthesis, while it alone had no influence on the cGMP formation in intact tissues. Pretreatment with L-NAME abolished the recovery of cGMP by irsogladine. Furthermore, irsogladine ameliorated the NH(2)Cl-induced decrease in gastric mucosal blood flow, which was also reversed by pretreatment with L-NAME. These findings suggest that the improvement of the decrease in mucosal blood flow subsequent to the disturbance of gastric nitric oxide synthesis is involved in the protective effect of irsogladine on gastric mucosal lesions caused by NH(2)Cl.

Ammonia aggravates stress-induced gastric mucosal oxidative injury through the cancellation of cytoprotective heat shock protein 70.

The relationship between Helicobacter pylori colonization and the formation of stress-induced gastric mucosal injury remains unknown. Since ammonia (NH(3)) is known as one of the injurious factors in H. pylori-colonized gastric mucosa, the present study is designed to investigate the level of stress-induced gastric mucosal oxidative injury with or without intragastric NH(3) overloading. To apply emotional stress, the communication box paradigm was used in the mouse model. Mice (C57BL/6, male) were pretreated with distilled water (responder-H(2)O) or 0.01% NH(3) (responder-NH(3)) through a gastric tube once a day for a week. Emotional stress was then applied to the responder mice for 3 h per day for 3 d by watching and hearing the behavior of the sender mice subjected to electric shocks to the feet (2 mA, 10 s, 50 s interval). After the communication box protocol, the tissue MPO activity, the contents of TBA-reactive substances (TBARS), and the level of gastric mucosal HSP70 were examined. Responder-NH(3) mice developed more severe gastric lesions than the responder-H(2)O subjects. MPO activity and TBARS contents were enhanced significantly in the responder-NH(3) group compared with the responder-H(2)O subjects. Although the contents of HSP70 in the gastric mucosa increased in the responder-H(2)O group compared with the control-H(2)O animals, they were significantly attenuated in the responder-NH(3) mice. Excess intragastric NH(3) was able to enhance the formation of emotional stress-induced gastric mucosal lesions. This injury may be associated with the enhanced production of oxygen free radicals from accumulated neutrophils under the NH(3)-mediated cancellation of gastric mucosal cytoprotective HSP70.

Circadian rhythm of melatonin and prostaglandin in modulation of stress-induced gastric mucosal lesions in rats.

We previously demonstrated the circadian variation of water-immersion restraint stress (WRS)-induced gastric mucosal lesions in rats. To investigate the roles of melatonin and prostaglandin in the gastric mucosa in circadian modulation of WRS. Fasted rats were subjected to 4-h WRS during both the diurnal and nocturnal phases of a light/dark cycle. Mucosal lesions, serum melatonin concentrations, mucosal generation of prostaglandin E2 (PGE2) and mucosal gene expressions of cyclooxygenase (COX)-1 and -2 were evaluated. Lesion area after 4-h stress during the dark phase was significantly smaller than that in light-phase controls. Serum melatonin concentration in control rats during the light phase was significantly increased 4 h after WRS, but PGE2 generation was decreased by 48% as compared to that in intact mucosa before stress. In the dark phase, melatonin concentration after 4-h WRS was significantly depressed as compared with the control level at the corresponding time. PGE2 concentrations after 4-h WRS in the dark phase were not decreased compared with the control level at the corresponding time, although PGE2 level was significantly lower than that in light-phase controls. Expression of COX-1 and COX-2 mRNA was detected after exposure to stress in both the light and dark phases. These results suggest that circadian rhythm has an important role in the formation of stress-induced gastric mucosal lesions in rats. The circadian rhythm of melatonin responses and PGE2 generation may contribute to nocturnal/diurnal rhythmicity of gastric mucosal defences between day and night.

Polaprezinc attenuates the Helicobacter pylori-induced gastric mucosal leucocyte activation in Mongolian gerbils--a study using intravital videomicroscopy.

We previously demonstrated that Helicobacter pylori colonization evokes gastric mucosal inflammation and an extensive increase in lipid peroxides and glutathione in Mongolian gerbils. Zinc and its derivative, polaprezinc, have been reported to be potent antioxidants in gastric mucosa. To examine the effect of polaprezinc on gastric mucosal oxidative inflammation in H. pylori-colonized Mongolian gerbils. Sixty-eight male Mongolian gerbils were orally inoculated with H. pylori (ATCC43504, 5 x 10(8) CFUs/gerbil; H. pylori group) and 35 gerbils were inoculated with the culture media (control group). Twenty-two gerbils in the H. pylori and 13 gerbils in the control group were fed with diets containing polaprezinc (0.06%, 100 mg/kg, 10 times the usual clinical dose) (H. pylori + polaprezinc group, polaprezinc group). The remaining gerbils were fed a standard laboratory chow diet. Neutrophil infiltration, assessed histologically and by the activity of myeloperoxidase, the contents of CXC-chemokine (GRO/CINC-1-like protein) and the contents of thiobarbituric acid-reactive substances, was evaluated in each group 12 weeks after the inoculation. Separately, gastric mucosal leucocyte activation and capillary perfusion were also assessed using intravital microscopy 2, 4, 8 and 12 weeks after the inoculation. In all H. pylori-inoculated animals, the bacterial infection persisted throughout the experimental period. Gastric mucosal lesion formation in the H. pylori group was significantly inhibited in the H. pylori + polaprezinc group. Elevated levels of myeloperoxidase activity, GRO/CINC-1 and thiobarbituric acid-reactive substances in the H. pylori group at 12 weeks were attenuated significantly by polaprezinc treatment. Enhanced levels of venular leucocyte activation observed in the H. pylori group were attenuated significantly in the H. pylori + polaprezinc group during both the early phase (2 weeks) and late phase (12 weeks). Polaprezinc inhibited H. pylori-associated gastric mucosal oxidative inflammation, including initial micro-vascular leucocyte activation, in Mongolian gerbils.

Roles of nocturnal melatonin and the pineal gland in modulation of water-immersion restraint stress-induced gastric mucosal lesions in rats.

The roles of melatonin and the pineal gland in the circadian variation of water-immersion restraint stress-induced gastric mucosal lesions in rats were investigated. Fasted rats were subjected to water-immersion restraint stress during both the diurnal and nocturnal phases of a light:dark cycle. Pinealectomized and sham-operated rats were also subjected to water-immersion restraint stress at night. The lesion area after 4 hr of stress during the dark phase was significantly lower than in light-phase controls. Pinealectomy increased the lesion area in the dark phase, compared to the sham operation, but this effect was counteracted by intracisternal melatonin preadministration at a dose of 100 ng/rat. Melatonin concentrations in control rats during the light phase were significantly increased 4 hr after water-immersion restraint stress. In contrast, melatonin concentrations 4 hr after water-immersion restraint stress in the dark phase were significantly depressed compared with the control levels at the corresponding time. Melatonin levels after stress exposure were markedly decreased in pinealectomized rats as compared with sham-operated rats. These results suggest that circadian rhythm has an important role in the formation of stress-induced gastric mucosal lesions in rats and that melatonin responses to water-immersion restraint stress differ between day and night. The pineal gland modulates the stress response and melatonin contributes to gastric protection via a mechanism involving the central nervous system.

Preventive effect of ebselen on acute gastric mucosal lesion development in rats treated with compound 48/80

The preventive effect of ebselen, a seleno-organic compound, which is known to possess glutathione peroxidase-like activity and antioxidative and anti-inflammatory properties, on the development of acute gastric mucosal lesions was examined in rats with a single injection of compound 48/80 (0.75 mg/kg, i.p.), a mast cell degranulator. Pre-administration of ebselen (p.o.) at a dose of 50 or 100 mg/kg, but not 10 mg/kg, prevented gastric mucosal lesion development at 3 h, but not gastric mucosal lesion formation at 0.5 h, after compound 48/80 injection, although any dose of pre-administered ebselen did not affect decreased gastric mucosal blood flow and increased serum serotonin and histamine concentrations found at 0.5 and 3 h after compound 48/80 injection. A decrease in Se-glutathione peroxidase activity and increases in the activities of myeloperoxidase, an index of tissue neutrophil infiltration, and xanthine oxidase and the concentration of thiobarbituric acid reactive substances, an index of lipid peroxidation, were found in gastric mucosal tissues at 0.5 h after compound 48/80 injection and these changes were further enhanced at 3 h. Pre-administration of ebselen (p.o.) at a dose of 50 or 100 mg/kg, but not 10 mg/kg, attenuated all these changes found at 3 h after compound 48/80 injection. These preventive effects of ebselen occurred in a dose-dependent manner. The present results indicate that pre-administered ebselen prevents the development of compound 48/80-induced acute gastric mucosal lesions in rats, and suggest that this preventive effect of ebselen could be due to its glutathione peroxidase-like activity and antioxidative and anti-inflammatory properties.

Vagus-mediated activation of mucosal mast cells in the stomach: Effect of ketotifen on gastric mucosal lesion formation and acid secretion induced by a high dose of intracisternal TRH analogue

TRH analogue, RX 77368, injected intracisternally (i.c.) at high dose (3 μg/rat) produces gastric mucosal lesion formation through vagal-dependent pathway. The gastric mucosal hyperemia induced by i.c. RX 77368 was shown to be mediated by muscarinic vagal efferent fibres and mast cells. Furthermore, electrical vagal stimulation was observed to induce gastric mucosal mast cell degranulation. The aim of the study was to assess the influence of ketotifen, a mast cell stabilizer, on RX 77368-induced gastric lesion formation and gastric acid secretion. RX 77368 (3 μg, i.c.) or vehicle (10 μL, i.c.) was delivered 240 min prior to the sacrifice of the animals. Ketotifen or vehicle (0.9% NaCl, 0.5 mL) was injected intraperitoneally (i.p.) at a dose of 10 mg.kg –1 30 min before RX 77368 injection. The extent of mucosal damage was planimetrically measured by a video image analyzer (ASK Ltd., Budapest) device. In the gastric acid secretion studies, the rats were pretreated with ketotifen (10 mg.kg –1, i.p.) or vehicle (0.9% NaCl, 0.5 mL, i.p.), 30 min later pylorus-ligation was performed and RX 77368 (3 μg, i.c.) or vehicle (0.9% NaCl, 10 μL, i.c.) was injected. The rats were killed 240 min after i.c. injection, and the gastric acid secretion was measured through the titration of gastric contents with 0.1 N NaOH to pH 7.0. RX 77368 (3 μg, i.c.) resulted in a gastric mucosal lesion formation involving 8.2% of the corpus mucosa ( n = 7). Ketotifen elicited an 85% inhibition on the development of mucosal lesions ( n = 7, P < 0.001) whereas ketotifen alone had no effect on the lesion formation in the mucosa ( n = 7). The RX 77368 induced increase of gastric acid secretion was not influenced by ketotifen pretreatment in 4-h pylorus-ligated animals. Central vagal activation induced mucosal lesion formation is mediated by the activation of mucosal mast cells in the stomach. Mast cell inhibition by ketotifen does not influence gastric acid secretion induced by i.c. TRH analogue in 4-h pylorus-ligated rats.