Aspirin-induced Gastric Mucosal Lesions Research Articles

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

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

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

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.

Attenuation of gastric mucosal inflammation induced by aspirin through activation of A2Aadenosine receptor in rats

To determine whether a specific adenosine A(2A) receptor agonist (ATL-146e) can ameliorate aspirin-induced gastric mucosal lesions in rats, and reduce neutrophil accumulation and production of pro-inflammatory cytokines. Gastric lesions were produced by oral gavage of aspirin (200 mg/kg) and HCl (0.15 mol/L, 8.0 mL/kg). 4-{3-[6-Amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-cyclohexanecarboxylic acid methyl ester (ATL-146e, 2.5-5 mug/kg, IP) was injected 30 min before the administration of aspirin. Tissue myeloperoxidase (MPO) concentration in gastric mucosa was measured as an index of neutrophil infiltration. Gastric mucosal concentrations of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) were determined by ELISA. Also, we examined the effect of ATL-146e on tissue prostaglandin E2 (PGE2) production and gastric secretion. Intragastric administration of aspirin induced multiple hemorrhagic erosions in rat gastric mucosa. The total length of gastric erosions (ulcer index) in control rats was 29.8+/-7.75 mm and was reduced to 3.8+/-1.42 mm after pretreatment with 5.0 g/kg ATL-146e (P<0.01). The gastric contents of MPO and pro-inflammatory cytokines were all increased after the administration of aspirin and reduced to nearly normal levels by ATL-146e. Gastric mucosal PGE2 concentration was not affected by intraperitoneal injection of ATL-146e. The specific adenosine A(2A) receptor agonist, ATL-146e, has potent anti-ulcer effects presumably mediated by its anti-inflammatory properties.

Rolipram, a Specific Type IV Phosphodiesterase Inhibitor, Ameliorates Aspirin-Induced Gastric Mucosal Injury in Rats

Inhibition of type IV phosphodiesterase (PDE IV) activity reduces the production of various proinflammatory cytokine and suppresses neutrophil activation. Nonsteroidal anti-inflammatory drugs such as aspirin induce gastric mucosal lesions. In the pathogenesis of aspirin-induced gastric mucosal lesion, the contributions, of activated inflammatory cells and proinflammatory cytokine production are critical. The specific PDE IV inhibitor rolipram is known to be a potent inhibitor of inflammation by increasing intracellular cyclic AMP in leukocytes. The aim of the present study was to determine whether rolipram can ameliorate aspirin-induced gastric mucosal lesions in rats and whether the agent can inhibit the inrease in neutrophil accumulation and the production of proinflammatory cytokines. Gastric lesions were produced by administration of aspirin (200 mg/kg) and HCI (0.15 N; 8.0 ml/kg). Rolipram was injected 30 min before aspirin administration. The tissue myeloperoxidase concentration in gastric mucosa was measured as an indicat or of neutrophil infiltration. The gastric mucosal concentrations of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) were determined by ELISA. The intragastric administration of aspirin induced multiple hemorrhagic erosions in rat gastric mucosa. Gastric mucosal lesions induced by aspirin were significantly inhibited by treatment with rolipram. The mucosal myeloperoxidase concentration was also suppressed by rolipram. Increases in the gastric content of TNF-alpha and IL-1beta after aspirin administration were inhibited by pretreatment with rolipram. We demonstrated that the specific type IV PDE inhibitor, rolipram, could have a potent antiulcer effect, presumably mediated by its anti-inflammatory properties.

Potent Antiulcerogenic Activity of Methanol Extract of Cissus quadrangularis by Antioxidative Mechanism

Oxidative stress is considered to be one of the important etiological factors invarious diseases including gastric ulcers. The mechanism of aspirin induced gastric lesion ismediated through lipid peroxidation. The effects of Cissus quadrangularis extract on aspirin-induced ulceration in rats with respect to its antioxidant status, lipid peroxidation, quantityof mucus and alkaline phosphatase and myeloperoxidase (MPO) activities was estimated.Cissus quadrangularis facilitated the healing of experimental gastric ulcer by increasedmucus content, antioxidant defense enzyme activity and decreased MPO activity and lipidperoxides levels in the gastric mucosa. These results indicate that Cissus quadrangularis extract protects against aspirin-induced gastric mucosal lesions in rats possibly through itsantioxidative action.

Effects of pectin-induced passive linkage of gastric H + on the gastric acid secretion and on the development of ethanol- and salicylate-induced gastric mucosal lesions in rats

The aim of this study was to evaluate the effects of intragastrically given pectin-induced physicochemical properties and actions on active gastric acid secretion and on the development of ethanol- and aspirin-induced gastric mucosal lesions. The observations were carried out on CFY-strain rats, fasted for 24 h before the experiments with water ad libitum. The observations were carried out in two experimental series. A) The gastric mucosal lesions were produced by intragastrically given 96% ethanol or aspirin prepared with 0.2 M HCl. Different doses of pectin (100, 50 and 25 mg.kg –1, respectively) were administered intragastrically 30 min before giving necrotizing agents. The number of gastric lesions was noted 1 h after the administration, while the severity of gastric mucosal lesions was scored by semi-quantitative scale. B) The effects of pectin were studied on the volume and H + secretion of the stomach in 4-h pylorus-ligated rats. It has been found that: 1) the gastric mucosal lesions could be produced in 100% of rats by the application of both necrotizing agents. 2) Pectin in doses of 50–100 mg.kg –1 increased the number of gastric mucosal lesions in both models, while no increase was produced by the application of 25-mg.kg –1 dose. 3) The severity of mucosal lesions increased significantly after the administration of all doses of pectin. 4) The pectin-induced increase of gastric lesions (number) showed a dose-response effect. 5) The pectin produced a significant increase in the volume of gastric secretion and gastric H + secretion. It has been concluded that: a) pectin-induced physicochemical changes are able to enhance the aggression to gastric mucosa produced by ethanol and aspirin; b) a positive correlation exists between the linkage of H + to pectin and significant active metabolic response in the rat stomach; c) pectin alone stimulates the active metabolic process of the gastric H + secretion.

Effect of a combination of ecabet sodium and cimetidine on experimentally induced gastric lesions and gastric mucosal resistance to ulcerogenic agents in rats.

We studied the effect of single oral administration of ecabet sodium (ecabet), a gastroprotective agent, in combination with the histamine H2-receptor antagonist cimetidine on gastric acid secretion, mucosal prostaglandin E2 (PGE2) production and experimentally induced acute hemorrhagic gastric lesions in rats. The effect repeated administration of ecabet in combination with cimetidine on the vulnerability of gastric mucosa to the ulcerogenic agents 0.6N HCl and aspirin was also studied. In pylorus-ligated rats, oral administration of cimetidine reduced gastric acid secretion, whereas ecabet did not affect the cimetidine-induced reduction in acid secretion. On the other hand, ecabet increased the capacity of gastric mucosa to synthesize PGE2, while cimetidine showed no effect on this parameter either in the presence of absence of ecabet. Both ecabet and cimetidine inhibited the formation of aspirin-induced gastric mucosal lesions, and the combination of ecabet and cimetidine showed a more potent inhibition than either drug alone. After cessation of repeated administration of cimetidine, but not ecabet, the 0.6N HCl- and aspirin-induced gastric lesions were significantly aggravated. The co-administration of ecabet improved the cimetidine-induced aggravation of these gastric lesions. These results suggest that ecabet in combination with cimetidine augments the antiulcer effect of cimetidine and improves the cimetidine-induced increase in gastric mucosal vulnerability to the ulcerogenic agents.

Aspirin-induced acute gastric mucosal injury is a neutrophil-dependent process in rats.

Aspirin, one of the most widely used drugs in the world, consistently produces gastric mucosal injury, but the pathogenic mechanisms are incompletely understood. The present study was designed to determine the role of neutrophils in aspirin-induced acute gastric mucosal injury. Gastric mucosal lesions induced by acidified aspirin (300 mg/kg) were completely prevented in rats that had been rendered profoundly neutropenic by anti-neutrophil serum. Aspirin-induced acute gastric mucosal lesions were also significantly, albeit incompletely, reduced in rats that had been rendered moderately neutropenic by methotrexate. Moreover, in the methotrexate-induced neutropenia model, the neutropenia-associated mucosal protection against aspirin-induced injury could be reversed by leucovorin rescue. Aspirin caused a marked and statistically significant reduction in gastric mucosal 6-ketoprostaglandin F1 alpha synthesis, but no significant changes in gastric mucosal leukotriene synthesis. Thus no gastric mucosal lesions were observed in profoundly neutropenic rats that were treated with aspirin, despite the marked inhibition of prostaglandin synthesis. These findings demonstrate that aspirin-induced acute gastric mucosal injury is a neutrophil-dependent process.

Prevention of ethanol and aspirin-induced gastric mucosal lesions by paracetamol and salicylate in rats: role of endogenous prostaglandins.

Paracetamol or sodium salicylate given intragastrically 30 minutes before the administration of absolute ethanol or acidified aspirin dose-dependently reduced the formation of mucosal lesions. The generation of gastric mucosal prostaglandin-like activity increased with ethanol and was completely suppressed by acidified aspirin. Paracetamol or sodium salicylate given alone increased the generation of mucosal prostaglandin-like material. Indomethacin, the prostaglandin synthesis inhibitor, suppressed this effect and inhibited the protective influence of paracetamol or sodium salicylate on the production of gastric lesions.

Role of prostaglandin E2 on gastric ulcers induced by non-steroidal anti-inflammatory compounds (NOSAC).

We investigated the effect of indomethacin and aspirin on the prostaglandin E2 (PGE2) levels in rat gastric mucosa. In untreated controls, the PGE2 level was 1085 +/- 80 ng/g in the fundic- and 2435 +/- 339 ng/g in the antral mucosa; it was markedly reduced by indomethacin (6 or 20 mg/kg) in a dose-related manner prior to the formation of gastric ulcers. Aspirin (200 mg/kg) also decreased the mucosal PGE2 content. The simultaneous infusion of 5 microgram/kg 16, 16-dimethyl PGE2 and 20 mg/kg indomethacin inhibited the formation of gastric ulcers. Our experimental results suggested that the indomethacin- or aspirin-induced gastric mucosal lesions are due to a deficiency of endogenous mucosal PGE2.

Mechanism of Prevention of Aspirin-Induced Gastric Lesions by Bile Duct Ligation in the Rat

Gastric reflux of bile has been reported to be essential for the production of acute gastric mucosal lesions by intragastric aspirin in the rat. The purpose of the present study was to determine whether bile duct legation of pylorus ligation in the rat inhibits asprin-induced gastric lesions, and, if so, what the protective mechanisms are. Operations were performed under ether anesthesia. Asprin, 200 mg per kg, was instilled into the stomach 1/2 hr postsurgery (bile duct ligation or pylorus ligation). Four hours later the rats were killed, the stomachs were examined, and mucosal lesions were scored. Bile duct ligation, but not pylorus ligation, significantly protected against aspirin-induced gastric-lesions. Bile duct ligation, in pylorus-ligated rats, inhibited gastric acid output by 78%. Instilling HCl + aspirin in bile duct-ligated rats restored lesion formation. Shunting bile to the colon (to prevent bile reflux) did not prevent aspirin lesions. Salicylate determination, to ascertain whether bile duct ligation altered asprin absorption, revealed no significant differences between bile duct ligation and aspirin, shunt + aspirin, and sham shunt + aspirin in plasma and gastric tissue salicylate concentrations. (1) Bile duct legation protects against aspirin-induced gastric mucosal lesions by inhibiting gastric HCl secretion. As a corollary, a certain amount of acid in the stomach is necessary for aspirin-induced gastric lesions to form. (2) Bile reflux is not necessary for aspirn-induced gastric lesions in the rat.