Aspirin-induced Gastric Lesions Research Articles

Treatment effects of Shilajit on aspirin‐induced gastric lesions in rats

The present study investigated the effects of Shilajit extract on aspirin‐induced gastric lesions in rats. We evaluated macroscopic and histopathological lesions in the stomach, measured the activity of oxidative stress enzymes in gastric tissue homogenates, and assessed serum electrolytes and parameters of kidney and liver function. Forty‐five male rats were allocated to five groups: Normal control, positive control, omeprazole treatment, Shilajit treatment, and Shilajit control. The treatment period lasted for four consecutive days. The size and number of gastric lesions were significantly reduced in the Shilajit and omeprazole groups compared to the positive control group, indicating a reduction in mucosal damage and the severity of edema and leukocyte infiltration in tissue sections. A significant increase was observed in the levels of all oxidative stress parameters, except malondialdehyde, in rats treated with Shilajit and omeprazole compared to those in the positive control group. The effect of the aqueous extract of Shilajit was comparable to that of omeprazole. These results indicated the protective effects of Shilajit against aspirin‐induced gastric lesions.

Histological Study of the Caffeine Effect on Intact Gastric Mucosa and Induced Gastric Ulcer in Adult Male Albino Rats

Introduction: Gastric ulcer is a serious health problem of worldwide concern.Caffeine is affirmed globally as a safe dietary element as a result of its high antioxidant content.Aim of the Work: To assess the cytoprotective impact of caffeine on the intact gastric mucosa and aspirin-induced gastric ulcer in adult male albino rats.Materials and Methods: Forty-two adult male albino rats were divided into four groups. Group I (control group). Group II (caffeine group), received aqueous caffeine (300 mg /kg/day) by gastric tube. Group III, overnight fasted rats received aspirin solution (200 mg/kg/day) orally for 5 consecutive days, then rats were further subdivided equally into: Subgroup IIIa (gastric ulcer group), sacrificed six hours after the last aspirin dose, subgroup IIIb, left without treatment for 4 weeks and subgroup IIIc received caffeine orally for 4 weeks. Group IV (caffeine prophylactic group) before ulcer induction. Serum was maintained for antioxidants activity assay; total antioxidant capacity (TAC), prostaglandin (PGE2) and tumour necrotic factor-alpha (TNF-α).Specimens of stomach body were processed for light and electron microscopic studies. Morphometric and statistical analysis was done.Results: Light microscopic study of the gastric ulcer group depicted deep erosion, damage of parietal and chief cells with vacuolated cytoplasm and pyknotic nuclei, congested blood vessels and aggregated mononuclear inflammatory cells that were supported by a significant increase of (TNF-α) expression coupled to a significant decrease in PGE2 and TAC levels and a significant reduction of Periodic-Acid-Schiff reaction coupled to a significant increase in area percentage of collagen fibers upon aspirin administration.The ultrastructural assessment confirmed these distortions. Whereas, caffeine prophylactic and treated groups revealed greater improvement in the histological changes depicted previously.Conclusion:Caffeine has protective impacts on the intact gastric mucosa. Additionally, it alleviated aspirin-induced gastric mucosal lesions in adult male albino rats that might be related to its high antioxidant content

Gastroprotective effects of mumie on aspirin-induced gastric lesions in rats

The present research was carried out to investigate the influence of mumie aqueous extract on aspirin-induced gastric lesions in rats. Thirty-eight male animals were grouped as the following: Normal control received 1 ml normal saline; positive control received 1 ml normal saline; standard control received omeprazole (20 mg/kg); treatment received mumie (600 mg/kg). After 1 h all the rats (except the normal control group) were given 500 mg/kg aspirin to induce lesions. Four hours after lesion induction, the gastric injuries were assessed through the evaluation of the macroscopic appearance of lesions, histopathology, and parameters including malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPX), glutathione reductase (GR), and catalase in the gastric tissue homogenate. The gastric lesion area and number significantly decreased in mumie and omeprazole groups compared to the positive control group, which histopathologically showed decrease of mucosal damage, edema, and leukocyte infiltration. A significant increase in oxidative enzyme levels with a reduction in MDA concentration was seen in rats of mumie and omeprazole groups compared to the positive control group. The preventive effect of the mumie aqueous extract was comparable to that of omeprazole. These findings demonstrated the protective effects of mumie against aspirin-induced gastric lesions.

Mucus secretion and collagen fibres integrity are compromised in aspirin induced gastric lesion; protective role of Musa paradisiaca

The study investigated the healing effects of flavonoid-rich fraction of Musa paradisiaca fruit on the gastric corpus of Wistar rats following aspirin induced-gastric lesion. Ninety adult male Wistar rats were assigned to 6 groups. Gastric lesion was induced in groups B, C, D, E and F rats by administration of 400 mg/kg aspirin. After 24 hours, the extract of M. paradisiaca was administered to groups C, D and E at graded doses for 21 days. Group F rats received omeprazole at 1.8 mg/kg daily for 21 days. The rats were sacrificed on days 14, 21 and 28. Gastric tissues were fixed in neutral buffered formalin and processed by paraffin wax embedding. Sections were stained with haematoxylin and eosin, Masson’s trichrome and periodic acid-Schiff’s. There was a gradual restoration of the damaged epithelia in the treatment groups. Histomorphometric studies revealed a significant increase in the total thickness of mucosal layers in the treatment groups when compared with aspirin only group. There was a dose-dependent improvement in staining for mucins in the treatment groups. Also, the treatment groups displayed a progressively positive stain for deposition of collagen. It is concluded that M. paradisiaca significantly attenuated the damaging effects of aspirin on the gastric mucosa, probably via a mechanism involving increase in mucin secretion.

Aspirin-Induced Gastric Lesions Alters EGFR and PECAM-1 Immunoreactivity in Wistar Rats: Modulatory Action of Flavonoid Fraction of Musa Paradisiaca.

AIM:In this study, Epithelial Growth Factor Receptor and Platelet Endothelial Cell Adhesion Molecule-1 were localised to investigate the healing effects of a flavonoid-rich fraction of M. paradisiaca fruit in the gastric corpus of Wistar rats following aspirin-induced gastric lesion.MATERIALS AND METHODS:Mature, unripe fruits of M. paradisiaca were peeled; air dried, pulverised, extracted with 70% methanol, concentrated and partitioned. Ninety male Wistar rats were randomly assigned into 6 groups of 15 rats each. The gastric lesion was induced in groups B, C, D, E and F rats by administration of 400 mg/kg aspirin in distilled water. Group A received distilled water. After 24 hours, flavonoid fraction of M. paradisiaca was administered to groups C, D and E at 100, 200 and 400 mg/kg respectively for 21 days. Group F rats received omeprazole at 1.8 mg/kg for 21 days. Five rats from each group were anaesthetized with ketamine on days 14, 21 and 28. Gastric tissues were excised and fixed in Neutral buffered formalin. This was followed by paraffin wax embedding method and sections stained with haematoxylin and eosin and for immunolocalisation of EGFR and PECAM-1. Data were analysed using descriptive and inferential statistics.RESULTS:There was a significant difference in the ulcer index in the corpus of control and treated rats throughout the experimental period (p = 0.0001). H&E stained sections showed a gradual restoration of the epithelial lining in the treated groups. Immunohistochemical examination showed that M. paradisiaca significantly increased (p < 0.05) reactivity for both EGFR and CD31 across the treatment groups.CONCLUSION:The efficacy of Musa paradisiaca in attenuating the damaging effects of aspirin on the gastric mucosa was observed as there was a significantly increased reactivity for EGFR and PECAM-1 in the gastric corpus in a dose-dependent manner.

Microanatomical evaluation of flavonoid-rich fraction of Musa paradisiaca in Aspirin-induced gastric lesion

Aim: This study investigated the healing effects of a flavonoid-rich fraction of Musa paradisiaca (MP) fruit on the histomorphology and histomorphometry of the gastric corpus in Wistar rats following aspirin-induced gastric lesion. This was with a view to providing information on the alternative therapies of treating gastric ulcers using unripe fruits of MP. Materials and Methods: Ninety adult male Wistar rats were randomly assigned into 6 groups of 15 rats each. Aspirin at a dose of 400 mg/kg was dissolved in distilled water and administered as a single oral dose to induce gastric lesions in the test groups of rats. After 24 h, flavonoid fraction of MP was administered to groups C, D, and E at graded doses for 21 days, whereas group F rats received omeprazole at 1.8 mg/kg. On days 14, 21, and 28, five rats from each group were sacrificed. The pH value of the gastric contents was determined, gastric tissues were processed using paraffin wax embedding method; sections were stained with hematoxylin and eosin and Alcian blue/PAS. Data were analyzed using descriptive and inferential statistics. Results: Histomorphological and histomorphometric studies showed a restorative effect of flavonoid fraction of MP in all the treated groups of rats as there was a significant (P = 0.0001) (P = 0.0001) increase in the total mucosal and glandular mucosal layers when compared with the test control. There was a progressive and dose-dependent improvement in staining for mucus-secreting cells in the treated groups as well as a significant (P = 0.0001) increase in a number of cells in the treatment groups when compared with the control. Conclusion: MP attenuated the deleterious effects of aspirin on the stomach by strengthening mucosa defensive factors.

Co-lyophilized Aspirin with Trehalose Causes Less Injury to Human Gastric Cells and Gastric Mucosa of Rats.

Aspirin is one of the most popular NSAIDs worldwide because of its anti-inflammatory and anticoagulant effects, and however, gastrointestinal injury remains a major complication. We previously reported co-lyophilized aspirin/trehalose (Lyo A/T) decreased the aspirin-induced gastric lesions in dogs. This study investigated the mechanism of gastroprotective effects of trehalose in vitro and in vivo. The apoptotic assays were performed in a human gastric carcinoma cell line, which was treated with aspirin, mixed aspirin/trehalose (Mix A/T) or Lyo A/T. Gastric ulcer severity was examined after oral administration of drugs in rats. In addition, the mucosal tissue apoptotic status in drug-treated rats was evaluated. Molecular dynamics simulations and laser Raman spectroscopy were performed in order to examine the molecular properties of Lyo A/T. DNA fragmentation was detected in AGS cells that were treated with aspirin and Mix A/T, but not in the Lyo A/T-treated cells. There were fewer apoptotic cells in the Lyo A/T-treated cells than in the other cells. Gastric injury was reduced in rats that received oral Lyo A/T compared with the others, while PGE2 synthesis was equally decreased in all groups. TUNEL assay and immunohistochemistry of cleaved caspase-3 in the mucosal tissues also revealed that Lyo A/T treatment induced less apoptosis than the others. The Lyo A/T spectrum showed clear differences in several Raman bands compared with that of Mix A/T. Our data showed that co-lyophilization of aspirin with trehalose reduced gastric injury, potentially through suppression of aspirin-induced mucosal cell apoptosis while retaining its anti-inflammatory effects.

527 Carbon Monoxide and Hydrogen Sulfide: the Crosstalk in the Mechanism of Gastroprotection Against Aspirin-Induced Gastric Lesions

viability (n=3; p<0.05). Oxidative stress and autophagy were also documented in a murine EoE model, in which autophagy inhibition in vivo resulted in enhanced disease activity and morphological changes consistent with esophageal epithelial degeneration. Conclusions: Autophagy is activated in the epithelium of EoE patients and may serve a cytoprotective function. Our findings suggest that the inflammatory EoE microenvironment induces oxidative stress in epithelial cells, which subsequently activates autophagy to restore redox balance and maintain epithelial integrity.

Protective effect of Artemisia campestris extract against aspirin-induced gastric lesions and oxidative stress in rat

The present study aims at evaluating the antiulcer and antioxidant effect of Artemisia campestris aqueous extract (ACAE) as well as the mechanism of action involved in such gastroprotection. The use of LC/MS allowed the identification of 11 phenolic compounds and the colorimetric analysis demonstrated that the ACAE exhibited an important in vitro antioxidant activity. We first showed that in vivo ACAE protected against macroscopic and histological changes induced by aspirin in stomach mucosa. Aspirin administration was accompanied by an oxidative stress status assessed by an increase in malondialdehyde (MDA) level, a decrease in the content of sulfhydryl –(SH) groups and a depletion of antioxidant enzyme activities such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx). Pre-treatment with ACAE protected against aspirin-induced gastric oxidative stress. More importantly, aspirin administration increased plasma and tissue hydrogen peroxide (H2O2), free iron and calcium levels, while the ACAE pre-treatment reversed all the effects of aspirin-induced intracellular mediators. In conclusion, we suggest that Artemisia campestris aqueous extract has potent antiulcer and antioxidant properties. This gastroprotection offered by ACAE might be related partly to the safety of sulfhydryl group as well as its opposite effect on some intracellular mediators such as hydrogen peroxide, free iron and calcium.

Effect of ovarian sex hormones on non-steroidal anti-inflammatory drug-induced gastric lesions in female rats

Objective:The objective of the following study is to investigate the effect of ovarian sex hormones on gastric ulcer in female rats.Materials and Methods:Female rats were treated daily with estrogen (0.05 and 0.1 mg/kg), progesterone (2.0 and 5.0 mg/kg), combined estrogen (0.05 mg/kg) and progesterone (2.0 mg/kg), ranitidine (30 mg/kg) or vehicle for 7 days. Ulcers were induced with aspirin on 7th day. Four hours later, animals were sacrificed and stomach were removed for macroscopic and biochemical examination.Results:Estrogen in 0.05 and 0.1 doses showed 32% and 18% of ulcer inhibition, respectively, progesterone 09% and 14% inhibition in 2.0 and 5.0 mg/kg doses, respectively, whereas combined estrogen and progesterone showed 23% and ranitidine showed 60% inhibition. However, the inhibition attained and the stomach malondialdehyde and glutathione levels in sex hormone treated groups were not statistically significant when compared to control group.Conclusion:At the tested doses, these ovarian sex hormones neither worsen nor protect against aspirin-induced gastric lesions in female rats.

Protective role of hydrogen-rich water on aspirin-induced gastric mucosal damage in rats

To investigate the role of the hydrogen-rich water (HRW) in the prevention of aspirin-induced gastric mucosal injury in rats. Forty male rats were allocated into four groups: normal control group, HRW group, aspirin group, and HRW plus aspirin group. The protective efficacy was tested by determining the gastric mucosal damage score. Malondialdehyde (MDA), superoxide dismutase (SOD), myeloperoxidase (MPO), interleukin (IL)-06 and tumor necrosis factor (TNF)-α in gastric tissues were evaluated. The serum levels of IL-1β and TNF-α were also detected. Histopathology of gastric tissues and localization of Cyclooxygenase 2 (COX-2) were detected using hematoxylin and eosin staining and immunohistochemistry, respectively. Pretreatment with HRW obviously reduced aspirin-induced gastric damage scores (4.04 ± 0.492 vs 2.10 ± 0.437, P < 0.05). The oxidative stress levels of MDA and MPO in the gastric tissues increased significantly in the aspirin-treated group compared with the HRW group (2.43 ± 0.145 vs 1.79 ± 0.116 nmol/mg prot, P < 0.05 and 2.53 ± 0.238 vs 1.40 ± 0.208 U/g tissue, P < 0.05, respectively). HRW could obviously elevated the SOD levels in the gastric tissues (37.94 ± 8.44 vs 59.55 ± 9.02 nmol/mg prot, P < 0.05). Pretreatment with HRW significantly reduced IL-06 and TNF-α in the gastric tissues (46.65 ± 5.50 vs 32.15 ± 4.83 pg/mg, P < 0.05 and 1305.08 ± 101.23 vs 855.96 ± 93.22 pg/mg, P < 0.05), and IL-1β and TNF-α in the serum (505.38 ± 32.97 vs 343.37 ± 25.09 pg/mL, P < 0.05 and 264.53 ± 28.63 vs 114.96 ± 21.79 pg/mL, P < 0.05) compared to treatment with aspirin alone. HRW could significantly decrease the COX-2 expression in the gastric tissues (staining score: 8.4 ± 2.1 vs 2.9 ± 1.5, P < 0.05). HRW pretreatment alleviated the aspirin-induced gastric lesions by inhibiting the oxidative stress, inflammatory reaction and reducing the COX-2 in the gastric tissues.

Orally Administered Phosphatidic Acids and Lysophosphatidic Acids Ameliorate Aspirin-Induced Stomach Mucosal Injury in Mice

Recent investigations revealed that lysophosphatidic acid (LPA), a phospholipid with a growth factor-like activity, plays an important role in the integrity of the gastrointestinal tract epithelium. This paper attempts to clarify the effect of orally administered phosphatidic acid (PA) and LPA on aspirin-induced gastric lesions in mice. Phospholipids, a free fatty acid, a diacylglycerol and a triglyceride at 1 mM (5.7 μmol/kg body weight) or 0.1 mM were orally administered to mice 0.5 h before oral administration of aspirin (1.7 mmol/kg). The total length of lesions formed on the stomach wall was measured as a lesion index. Formation of LPA from PA in the mouse stomach was examined by in vitro (in stomach lavage fluid), ex vivo (in an isolated stomach) and in vivo (in the stomach of a living mouse) examinations of phospholipase activity. Palmitic acid, dioleoyl-glycerol, olive oil and lysophosphatidylcholine did not affect the aspirin-induced lesions. In contrast, phosphatidylcholine (1 mM), LPA (1 mM) and PA (0.1, 1 mM) significantly reduced the lesion index. Evidence for formation of LPA from PA in the stomach by gastric phospholipase A2 was obtained by in vitro, ex vivo and in vivo experiments. An LPA-specific receptor, LPA2, was found to be localized on the gastric surface-lining cells of mice. Pretreatment with PA-rich diets may prevent nonsteroidal anti-inflammatory drug-induced stomach ulcers.

Experimental research Effects of captopril on factors affecting gastric mucosal integrity in aspirin-induced gastric lesions in Sprague-Dawley rats

IntroductionCaptopril is an angiotensin-converting enzyme inhibitor, which is used as an antihypertensive agent and has shown antioxidant properties. This study aims at determining the effects of captopril on factors affecting gastric mucosal integrity in aspirin-induced gastric lesions.Material and methodsEighteen male Sprague-Dawley (200-250 g) rats that were given aspirin (40 mg/100 g body weight) were divided into three groups: the control, captopril (1 mg/100 g body weight daily) and ranitidine (2.5 mg/100 g body weight twice daily) groups. Ranitidine and captopril were given orally for 28 days. Rats in all groups were sacrificed and the parameters measured.ResultsCaptopril reduced gastric acidity, and increased gastric glutathione (GSH) and prostaglandin E2 (PGE2) significantly in comparison to the control group. Captopril also reduced malondialdehyde (MDA) and gastric lesions insignificantly compared to the control group. Ranitidine healed the lesions significantly compared to the control group. There was no difference between ranitidine and captopril on the severity of lesions, gastric acidity, MDA and GSH. Captopril increased PGE2 compared to ranitidine (p < 0.05).ConclusionsCaptopril has desirable effects on the factors affecting gastric mucosal integrity (acidity, PGE2 and GSH) and is comparable to ranitidine in ulcer healing.

Clopidogrel delays the healing of aspirin-induced gastric mucosal lesions in rats

Clopidogrel delays the healing of aspirin-induced gastric mucosal lesions in rats

Inhibitory effect of L-glutamine on the aspirin-induced gastric lesions in the rat.

Abstract The effects of an amino acid, L-glutamine, on aspirin-induced gastric lesions and gastric secretion were studied in either intact or pylorus-ligated rats. L-Glutamine had a pronounced inhibitory effect on gastric lesions induced by aspirin administered by oral, intraperitoneal, or intraduodenal routes to intact or pylorus-ligated rats. By the oral route the inhibition was dose-related. However, L-glutamine given either intraduodenally or intraperitoneally did not show any appreciable effects on gastric lesions induced by orally administered aspirin in pylorus-ligated rats. One mechanism of L-glutamine protection was inhibition of a back diffusion of gastric acid caused by aspirin and this was demonstrated in pylorus-ligated rats. The reduction in H+ and increase in Na+ concentrations in the lumen caused by aspirin was returned to normal by increasing doses of L-glutamine. In addition, L-glutamine was considered to inhibit the back diffusion of acid caused by pylorus ligation per se, because the amino-acid produced an increment of H+ and reduction of Na+ and K+ in comparison with the control group. The role of pepsin on L-glutamine protection was negligible.

Effect of probiotics on aspirin-induced gastric mucosal lesions

We aimed to investigate the role of a probiotic mixture, including 13 different bacteria, in the prevention of aspirin-induced gastric mucosal injury. Forty rats were allocated into 4 groups: normal control, aspirin, probiotic control, and probiotic plus aspirin. Normal control and aspirin groups received 0.2 ml of skim milk by daily gavage for 14 days. Probiotic control and probiotic plus aspirin groups were administered 0.2 ml/day of probiotic mixture (1.3 x 10(10) cfu/ml) suspended in skim milk by daily gavage for 14 days. On day 15, gastric lesions were induced by administration of aspirin (200 mg/kg) in the aspirin and probiotic plus aspirin groups. Normal control and probiotic control groups were given saline. Pretreatment with probiotic mixture reduced aspirin-induced gastric damage scores (4.50 ± 0.43 and 2.60 ± 0.40, p<0.01) and exerted tendency of downregulation of proinflammatory cytokines elicited by aspirin (p>0.05). We also found that the probiotic mixture increased sIgA production approximately 7.5-fold in the stomach, and significantly reduced the malondialdehyde (MDA) increase in the gastric mucosa elicited by aspirin (p<0.001). Additionally, pretreatment with the probiotic mixture alleviated aspirin-induced reduction of mast cell count in the gastric mucosa. Probiotic mixture pretreatment attenuates the aspirin-induced gastric lesions by reducing the lipid peroxidation, enhancing mucosal sIgA production, and stabilizing mucosal mast cell degranulation into the gastric mucosa.

T1069 Effect of Low-Dose Administration of Lansoprazole On the Gastric Mucosal Lesions Induced By Low-Dose Aspirin in Relation to Intragastric pH in Healthy Volunteers with Different CYP2C19 Genotypes

Backgrounds and Aims: Given the major role gastric acid plays in the development of aspirininduced gastric mucosal lesions, proton pump inhibitors (PPIs) are now employed as firstline therapy in treating aspirin-related gastrointestinal disorders. Low-dose PPIs are also expected to have a similar preventive effect on aspirin-induced gastric injury. PPIs are metabolized by CYP2C19 in the liver, and their therapeutic effects are influenced by CYP2C19 genotype status. However, the effect of low-dose PPI on aspirin-induced gastric mucosal injury in relation to gastric acidity in humans has not been examined. Here, we investigated the relationship between intragastric pH and aspirin-induced gastric mucosal lesions with regard to CYP2C19 genotype status in healthy subjects receiving aspirin with and without a low-dose administration of lansoprazole. Methods: Fifteen Helicobacter pylori-negative subjects with different CYP2C19 genotype statuses (5 RMs, 5 intermediate metabolizers [IMs], and 5 poor metabolizers [PMs]) were each administered a series of three 7-day regimens of 15 mg of lansoprazole alone, 100 mg of aspirin alone, and both 15 mg of lansoprazole and 100 mg aspirin, with the order randomized among individuals. A washout period of 2 weeks or more was provided between regimens. Gastric mucosal injury was endoscopically evaluated on day 7 of each dosing period based on the modified Lanza score (MLS). 24-hour intragastric pH monitoring was started after endoscopy. Results: Median values (range) of MLS were 0 (0-1) in controls, 0 (0-1) in subjects receiving 15 mg of lansoprazole alone, 3 (0-5) in subjects receiving aspirin alone, and 0 (0-1) in subjects receiving both aspirin and 15 mg of lansoprazole. Lansoprazole increased the intragastric pH and significantly prevented aspirin-induced gastric mucosal injury (p = 0.0009 for aspirin and lansoprazole 15 mg). MLSs were negatively correlated with 24-hour intragastric pH (r = -0.740, P < 0.0001), whereas aspirin had no effect on intragastric pH. With regard to treatment with aspirin and lansoprazole 15 mg, although median values of MLS did not differ among the three genotype groups, median values of intragastric pH during treatment with this regimen were higher in PMs than in RMs and IMs (P = 0.009 for RMs, P = 0.028 for IMs). Conclusion: We observed a significant relationship between 24-hour intragastric pH and grade of aspirin-induced gastric mucosal lesions. Further, the acid inhibition attained on administration of 15 mg of lansoprazole appeared sufficient to prevent aspirin-induced gastric mucosal damage, irrespective of CYP2C19 genotype status.

Prophylactic Effect of Rebamipide on Aspirin-Induced Gastric Lesions and Disruption of Tight Junctional Protein Zonula Occludens-1 Distribution

Aspirin and nonsteroidal anti-inflammatory agents are known to induce gastroduodenal complications such as ulcer, bleeding, and dyspepsia. In this study, we examined the prophylactic effect of rebamipide, an anti-ulcer agent with free-radical scavenging and antiinflammatory effect, on acidified aspirin-induced gastric mucosal injury in rats. In addition, we investigated the mucosal barrier functions disrupted by aspirin. Oral administration of acidified aspirin resulted in linear hemorrhagic erosions with increasing myeloperoxidase activity and thiobarbituric acid-reactive substance concentrations in the gastric mucosa. Rebamipide suppressed these acidified aspirin-induced gastric lesions and inflammatory changes significantly, and its protective effect was more potent in the case of repeated (twice daily for 3 days) treatment than single treatment before aspirin administration. Immunostaining of zonula occludens (ZO)-1, one of the tight junctional proteins, was strengthened in rat gastric mucosa after repeated administration of rebamipide. In addition, aspirin induced the increasing transport of fluorescine isothiocyanate-labeled dextrans with localized disruption and decreased expression of ZO-1 protein on rat gastric mucosal cell line RGM-1. Rebamipide effectively prevented aspirin-induced permeability changes and disruption of ZO-1 distribution. These results suggest that rebamipide protects against aspirin-induced gastric mucosal lesions by preserving gastric epithelial cell-to cell integrity in addition to the anti-inflammatory effects.

Intragastric Nitroglycerin at a Vasodilatory Dose Attenuates Acidified Aspirin-Induced Gastric Mucosal Injury

Clinical studies reveal that aspirin intake to prevent myocardial and cerebral ischemia is associated with a significant increase in upper gastrointestinal hemorrhage requiring hospitalization and that nitroglycerin or long-acting nitrates significantly lower this risk. Nitroglycerin can increase gastric blood flow and slow gastric emptying. We hypothesized that both features contribute to its gastroprotective property. Fasted anesthetized rats (Study 1) and conscious mice (Studies 2 to 4) received intragastric nitroglycerin or vehicle. The effects of these two treatments on various parameters were assessed in Study 1, on blood pressure and gastric blood flow; Study 2, on acidified aspirin-induced gastric mucosal lesions; and Study 3, on the weight of gastric content. In Study 4, the effect of nitroglycerin, vehicle, or vehicle plus saline, on acidified aspirin-induced gastric mucosal lesion was assessed. Compared with vehicle, nitroglycerin decreased blood pressure and produced a mild but significant increase in gastric vascular conductance, blood flow, and volume of gastric content. The number and length of gastric mucosal lesions induced by acidified aspirin were significantly attenuated by intragastric nitroglycerin in a vasodilatory dose. Exogenous saline in a volume equivalent to the increase produced by nitroglycerin, however, did not attenuate the lesions. These experimental data are consistent with the clinical observation that nitrates lower the risk of aspirin-induced gastrointestinal complications. Confirmation of the efficacy of nitroglycerin and nitrates in preventing such aspirin-induced complications in controlled trials is worthy of consideration by clinical investigators.

Attenuation of Gastric Mucosal Inflammation Induced by Aspirin Through Inhibition of Selective Type III Phospshodiesterase in Rats

Cilostazol, a selective type III phosphodiesterase inhibitor, is widely used for treatment of ischemic symptoms of peripheral vascular disease. Recent studies have reported that the mechanism of cilostazol is related to suppression of pro-inflammatory cytokine production and improvement of local microcirculation disturbances. The activation of inflammatory cells and pro-inflammatory cytokine production play critical roles in the pathogenesis of aspirin-induced gastric irritation. The aim of the present study was to determine whether cilostazol can ameliorate aspirin-induced gastric mucosal lesions in rats, reduce neutrophil accumulation, and reduce the production of pro-inflammatory cytokines. Gastric lesions were produced by oral gavage of aspirin (200 mg/kg) and HCl (0.15 N, 8.0 ml/kg). Cilostazol (1-10 mg/kg, IP) was injected 30 min before aspirin administration. Also, we measured the gastric mucosal concentrations of myeloperoxidase and interleukin-1 beta, tumor necrosis factor-alpha, and cytokine-induced neutrophil chemoattractants-1, as an index of neutrophil accumulation, and the pro-inflammatory cytokines. Cilostazol ameliorated the gastric mucosal lesions induced by aspirin administration (P<0.01). The gastric contents of myeloperoxidase and pro-inflammatory cytokines were all increased after aspirin administration and significantly reduced by cilostazol treatment. In this study, we demonstrated that a selective type III phosphodiesterase inhibitor, cilostazol, reduced aspirin-induced gastric inflammation and damage via suppression of the production of proinflammatory cytokines. Cilostazol may be useful for preventing gastric mucosal lesions induced by aspirin.