Indomethacin-induced Gastric Injury Research Articles

Protective effect of taurine on indomethacin-induced gastric mucosal injury.

It has been suggested that oxygen-derived free radicals play an important role in the pathophysiology of acute gastric ulceration induced by NSAIDs and ischemia-reperfusion. Taurine is hypothesized to exert its protective effect on NSAIDs-induced gastric injury by its antioxidant properties. The protective effect of taurine on indomethacin-induced gastric mucosal lesion and its protective mechanism were investigated. Intragastric administration of 25 mg/kg of indomethacin induced hemorrhagic lesions on the glandular stomach in rats. Pretreatment with 0.25 or 0.5 g/kg of taurine one day before or for 3 days significantly reduced gastric lesion formation and inhibited the elevation of lipid peroxide level in gastric mucosa. Both resting and FMLP-induced luminol-dependent chemiluminescence of rat peritoneal neutrophils increased immediately after treatment with indomethacin. Taurine (5-20 mM) inhibited chemiluminescence of neutrophils activated by FMLP. Human neutrophils (polymorphonuclear leukocytes) adhered to the confluent monolayer of human umbilical vein endothelial cells (HUVEC) after coincubation with indomethacin. This neutrophil adhesion induced by indomethacin to HUVEC was prevented by taurine in a dose-dependent manner. These results indicate that the protective effect of taurine against NSAIDs-induced gastric mucosal injury is due to its antioxidant effect, which inhibits lipid peroxidation and neutrophil activation.

Indomethacin-induced gastric injury and leukocyte adherence in arthritic versus healthy rats

Background & Aims : Arthritic patients are at greater risk of developing nonsteroidal anti-inflammatory drug (NSAID)-induced ulcers than other NSAID users. Leukocyte adherence to the vascular endothelium has been suggested to play an important role in the pathogenesis of experimental NSAID-associated gastropathy. The aim of this study was to examine the role of leukocyte adherence in NSAID-induced gastric injury in healthy and adjuvant-induced arthritic rats. Methods : Leukocyte adherence was examined using intravital microscopy before and after indomethacin administration. The role of CD18 and intercellular adhesion molecule 1 (ICAM-1) in indomethacin-induced gastric injury and leukocyte adherence was examined using specific monoclonal antibodies against these molecules. Results : Indomethacin (5–10 mg/kg) caused significantly more gastric damage in arthritic than normal rats, and the former group had significantly greater levels of leukocyte adherence to mesenteric postcapillary venules under basal conditions. Dexamethasone markedly reduced basal and indomethacin-induced leukocyte adherence and the extent of gastric damage. In arthritic rats, pretreatment with a monoclonal antibody directed against ICAM-1 significantly reduced gastric damage and leukocyte adherence to the levels observed in healthy rats, whereas an antibody directed against CD18 had no effect. Conclusions : Indomethacin-induced damage in healthy and arthritic rats is largely dependent on ICAM-1 expression. The increased susceptibility of arthritic rats to indomethacin-induced gastric injury may be partly related to elevated levels of ICAM-1-dependent leukocyte adherence.

Tumor necrosis factor α receptor-antagonists protect against indomethacin-induced gastric mucosal injury in rats

Tumor necrosis factor α receptor-antagonists protect against indomethacin-induced gastric mucosal injury in rats

Role of tumor necrosis factor α release and leukocyte margination in indomethacin-induced gastric injury in rats

Background/Aims: Several studies have shown that polymorphonuclear neutrophil leukocyte (PMN) margination is an early and critical event in the pathogenesis of gastric mucosal injury caused by nonsteroidal anti-inflammatory drugs. Tumor necrosis factor (TNF) α is a proinflammatory cytokine that causes PMN margination by up-regulating expression of adhesion molecules on both PMN and endothelial cells. This study investigated whether substances that modulate TNF synthesis and release influence PMN margination and indomethacin-induced gastric damage. Methods: Rats were treated with several doses of indomethacin alone or in association with substances known to increase (interleukin 2 and lipopolysaccharide) or inhibit (pentoxifylline, dexamethasone, granulocyte colony-stimulating factor [G-CSF]) TNF synthesis and release. Results: Indomethacin administration caused dose-dependent damage and increased PMN margination and plasma TNF concentrations. Pretreatment with interleukin 2 and lipopolysaccharide significantly increased TNF release, PMN margination, and gastric mucosal damage, but administration of dexamethasone, pentoxifylline, and G-CSF provided almost total protection. The administration of G-CSF alone caused a significant increase in gastric PMN margination but protected against the indomethacin-induced gastropathy. Conclusions: Agents that regulate TNF synthesis and release influence gastric susceptibility to indomethacin by modulating PMN margination. G-CSF increased PMN infiltration but protected against the mucosal injury, suggesting that PMN margination alone is not sufficient to induce mucosal damage.

Nonsteroidal Anti-Inflammatory Drug-Induced Enteropathy: Case Discussion and Review of the Literature

Nonsteroidal Anti-Inflammatory Drug-Induced Enteropathy: Case Discussion and Review of the Literature

Role of oxygen radicals in indomethacin-induced gastric mucosal microvascular injury in rats.

To investigate the pathogenesis of indomethacin-induced gastric mucosal injury, vascular injury was examined in the rat using Evans blue and monastral blue vascular tracers. Extravasation of intravenously injected Evans blue into the gastric mucosa was used as an indicator of vascular permeability. Monastral blue was used to demonstrate vascular injury morphologically. The extravasated content of Evans blue significantly increased and reached the maximum at 2 h after indomethacin administration. The increase in Evans blue content was significantly inhibited by the pretreatment with superoxide dismutase (SOD) and SOD + catalase, but not with catalase alone. Monastral blue-labeled damaged endothelial cells in the gastric mucosa also increased at 2 h after indomethacin administration, which increase was reduced by pretreatment with SOD and SOD + catalase. These results indicate that oxygen radicals, including the superoxide radical, play an important role in the microvascular injury induced by indomethacin, which in turn plays a primary role in the development of gross hemorrhagic erosions.

Role of endothelial adhesion molecules in NSAID-induced gastric mucosal injury

A number of recent studies have demonstrated that neutrophil adherence to the vascular endothelium is a critical early event in the pathogenesis of gastric mucosal injury induced by nonsteroidal anti-inflammatory drugs (NSAIDs). Although a role in this process for the leukocyte adhesion molecule, CD11/CD18, has been demonstrated, the involvement of endothelial adhesion molecules has not previously been examined. Therefore, using monoclonal antibodies directed against a number of endothelial adhesion molecules (ICAM-1, P-selectin, E-selectin), we studied the role of these molecules in the production of mucosal injury after indomethacin administration and in indomethacin-induced leukocyte adherence. As previously shown in the rabbit, anti-CD18 markedly reduced (by 75%) the severity of damage induced by indomethacin in the rat. Moreover, this antibody completely prevented indomethacin-induced leukocyte adherence. Similarly, anti-ICAM-1 significantly attenuated (by 74%) the severity of indomethacin-induced gastric injury while also markedly reducing leukocyte adherence (by 83%). Anti-P-selectin and anti-E-selectin produced only small (approximately 35%), but statistically significant, reductions of mucosal injury, but only anti-P-selectin significantly affected indomethacin-induced leukocyte adherence (by approximately 50%). These results demonstrate that indomethacin-induced leukocyte adherence and mucosal injury are dependent on the expression of CD18 and ICAM-1. P-selectin also appears to play a small, but important, role in these processes, whereas the role of E-selectin remains equivocal. These studies support the hypothesis that interactions at the leukocyte-endothelium interface are critical in the pathogenesis of NSAID-induced mucosal injury, and this interface may represent a rational target for therapies aimed at preventing this form of injury.

Immunopathology of NSAID‐Gastropathy: Inhibitory Effectsn of Interleukin‐I and Cyclosporin Aa

The present study demonstrates that CSA is capable of inhibiting indomethacin-induced leukocyte adherence to the vascular endothelium, and can reduce the severity of indomethacin-induced gastric mucosal injury. These results are therefore consistent with the hypothesis that leukocyte (particularly neutrophil) adherence is a critical event in the pathogenesis of NSAID-induced gastropathy. The mechanism through which CSA inhibits leukocyte adherence is not clear, and warrants further investigation. This study also confirmed the protective effects of IL-1 in experimental NSAID-gastropathy, and demonstrates that one of the ways the IL-1 may protect the mucosa is through its ability to inhibit the release of proinflammatory mediators (e.g., PAF) and promote the release of antiinflammatory mediators (e.g., nitric oxide). IL-1 modulated the release of these mediators from peritoneal mast cells at doses in the pg/ml to ng/ml range. IL-1 can inhibit the ability of neutrophils to respond to chemotactic stimuli and can prevent LTB4-induced neutropenia. Inhibition of neutrophil function by IL-1 may therefore account for its ability to reduce NSAID-induced gastric mucosal injury. Whether or not effects of IL-1 on the production of mediators such as nitric oxide and PAF is an underlying mechanism for the inhibitory effects on neutrophil function remains to be determined.

Mechanisms underlying the protective effects of interleukin 1 in experimental nonsteroidal anti-inflammatory drug gastropathy

Interleukin 1 (IL-1) has been shown to reduce the severity of experimental gastroduodenal ulceration, but the mechanism of action is unclear. The present study examined the possibility that the mechanism underlying the protective effects of IL-1 in experimental nonsteroidal anti-inflammatory drug (NSAID)-induced gastropathy is related to effects on gastric acid secretion, on prostaglandin synthesis, and/or on neutrophil function. IL-1 alpha and IL-1 beta dose-dependently (1-10 micrograms/kg) reduced the severity of gastric damage induced by indomethacin, whereas tumor necrosis factor alpha (1-10 micrograms/kg) had no effect. These effects of IL-1 were not completely attributable to a reduction in the volume or acidity of gastric secretion during the 1-hour pretreatment period. Whereas IL-1 alpha and IL-1 beta significantly inhibited pentagastrin-stimulated acid secretion, the dose-response relationship and time course of actions suggested that effects on acid secretion did not fully account for the ability of these agents to reduce indomethacin-induced gastric injury. The maximally effective dose of IL-1 beta (10 micrograms/kg) in terms of reduction of indomethacin-induced gastric injury did not significantly affect gastric prostaglandin synthesis. Neutrophil function was assessed using two in vivo assays. IL-1 beta inhibited migration of neutrophils in response to intradermal injections of N-formyl-methionyl-leucyl-phenylalanine and leukotriene B4 (LTB4) and dose-dependently (0.1-10 micrograms/kg) inhibited LTB4-induced neutropenia. These effects could be mimicked by dexamethasone (1 mg/kg SC), which inhibited the neutropenic response to LTB4 and significantly (P less than 0.001) reduced the severity of indomethacin-induced gastric damage. Both IL-1 beta and dexamethasone could significantly reduce the extent of histologically detectable leukocyte margination within the gastric mucosal microcirculation after indomethacin administration. The results of this study suggest that effects of IL-1 on gastric acid secretion or prostaglandin synthesis do not fully account for its ability to reduce the severity of experimental NSAID-induced gastropathy, whereas inhibitory effects of IL-1 on neutrophil function may contribute significantly to its protective actions. (Gastroenterology 1992 Apr;102(4 Pt 1):1176-85)

Mechanisms underlying the protective effects of interleukin 1 in experimental nonsteroidal anti-inflammatory drug gastropathy

Interleukin 1 (IL-1) has been shown to reduce the severity of experimental gastroduodenal ulceration, but the mechanism of action is unclear. The present study examined the possibility that the mechanism underlying the protective effects of IL-1 in experimental nonsteroidal anti-inflammatory drug (NSAID)-induced gastropathy is related to effects on gastric acid secretion, on prostaglandin synthesis, and/or on neutrophil function. IL-1α and IL-1β dose-dependently (1–10 μg/kg) reduced the severity of gastric damage induced by indomethacin, whereas tumor necrosis factor a (1–10 μg/kg) had no effect. These effects of IL-1 were not completely attributable to a reduction in the volume or acidity of gastric secretion during the 1-hour pretreatment period. Whereas IL-1α and IL-1β significantly inhibited pentagastrin-stimulated acid secretion, the dose-response relationship and time course of actions suggested that effects on acid secretion did not fully account for the ability of these agents to reduce indomethacin-induced gastric injury. The maximally effective dose of IL-1β (10 μg/ kg) in terms of reduction of indomethacin-induced gastric injury did not significantly affect gastric prostaglandin synthesis. Neutrophil function was assessed using two in vivo assays. IL-1β inhibited migration of neutrophils in response to intradermal injections of N-formyl-methionyl-leucyl-phenylalanine and leukotriene B4 (LTB4) and dose-dependently (0.1–10 ug/kg) inhibited LTB4-induced neutropenia. These effects could be mimicked by dexamethasone (1 mg/kg SC), which inhibited the neutropenic response to LTB4 and significantly (P < 0.001) reduced the severity of indomethacin-induced gastric damage. Both IL-1β and dexamethasone could significantly reduce the extent of histologically detectable leukocyte margination within the gastric mucosal microcirculation after indomethacin administration. The results of this study suggest that effects of IL-1 on gastric acid secretion or prostaglandin synthesis do not fully account for its ability to reduce the severity of experimental NSAID-induced gastropathy, whereas inhibitory effects of IL-1 on neutrophil function may contribute significantly to its protective actions.

Role of oxygen-derived free radicals in indomethacin-induced gastric injury

The role of oxygen-derived free radicals in the pathogenesis of acute gastric ulceration induced by indomethacin (Indo) was investigated in rats. Gastric damage was assessed by blood-to-lumen leakage of 51Cr-EDTA, as well as by measuring the extent of macroscopically visible hemorrhagic lesions. The stomach was perfused with isotonic saline for 30 min, followed by Indo (10 mg/ml for 30 min) and HCl (100 mM for 60 min). Rats were given a continuous intravenous infusion of the antioxidant enzymes superoxide dismutase (SOD) or catalase or the iron-chelating agent deferoxamine. Additional rats received an intravenous infusion of the vehicle (control group) or were pretreated with prostaglandin E2 (100 micrograms/kg ip) or allopurinol (50 mg/kg po). Exposure of the stomach to Indo caused a fourfold increase in 51Cr-EDTA leakage compared with that observed in rats receiving only the vehicle for Indo. Subsequent exposure of the stomach to HCl resulted in a further twofold increase in 51Cr-EDTA leakage. Treatment with SOD, catalase, or deferoxamine significantly (P less than 0.05) reduced 51Cr-EDTA leakage during the intragastric perfusion with Indo and during the subsequent exposure to HCl. Pretreatment with PGE2 reduced 51Cr-EDTA leakage during perfusion with HCl only. Pretreatment with allopurinol did not significantly affect 51Cr-EDTA leakage at any time during the experiment. In addition to reducing the leakage of 51Cr-EDTA into the gastric lumen, SOD, catalase, and PGE2 significantly reduced the extent of macroscopically visible mucosal damage (P less than 0.05). These results support the hypothesis that oxygen-derived free radicals, probably derived from neutrophils, contribute to the pathogenesis of Indo-induced ulceration.

Neomycin prevents indomethacin-induced gastric peristalsis and mucosal injury in the rat.

Inhibition of prostaglandin synthesis together with vagally mediated peristaltic contractions are essential if mucosal injury is to occur in the stomach of indomethacin-treated rats. The neomycin group of antibiotics has been shown to interfere with acetylcholine release. Agents blocking peristalsis have been demonstrated to prevent mucosal injury. We postulated that neomycin might inhibit peristalsis and prevent lesion formation. The effect of oral neomycin and bacitracin on gastric wall tone and peristaltic response to indomethacin were assessed and related to the lesion score. Bacitracin had no effect on either response and severe injury occurred. Neomycin did not block the tonal response to indomethacin but abolished peristalsis and no injury occurred. Induction of peristalsis with insulin in neomycin-indomethacin treated rats restored mucosal injury. It is concluded that neuromuscular blockade by neomycin prevented mucosal lesions by preventing peristalsis and not by impairing the ability of indomethacin to inhibit prostaglandin synthesis.

Protective effects of prostaglandins against ulcerogenic activity of indomethacin during different stages of erosion development in rat stomach. Role of acid and bicarbonate secretion.

Prostaglandin E2 (PGE2) and PGF2 beta decreased the gastric erosive activity of orally administered indomethacin in a dose-dependent manner, when given as a continuous intravenous infusion in the conscious rat. PGE2 protected both during the initial stage of erosion induction and during the later outgrowth to larger erosions. Moreover PGE2 was able to stop the eroding process at any stage as long as the infusion continued. Both PGs were protective only in doses which also reduced the histamine-stimulated acid secretion. PGE2 protected the stomach against indomethacin-induced erosions even in the presence of exogenously administered acid. An infusion of PGE2 stimulated the secretion of bicarbonate in the stomach during some minutes but had no effect during prolonged infusion. These results suggest that, although effects on secretion of acid and bicarbonate were found, these effects cannot be the (only) explanation for the cytoprotective effects observed. Furthermore the protective effect of PGE2 is not confined to any specific stage of the development of indomethacin-induced gastric injury.