Bleeding and delayed healing of ulcers are well recognized clinical problems associated with the use of aspirin and other nonsteroidal antiinflammatory drugs, which have been attributed to their antiaggregatory effects on platelets. We hypothesized that antiplatelet drugs might interfere with gastric ulcer healing by suppressing the release of growth factors, such as vascular endothelial growth factor (VEGF), from platelets. Gastric ulcers were induced in rats by serosal application of acetic acid. Daily oral treatment with vehicle, aspirin, or ticlopidine (an ADP receptor antagonist) was started 3 days later and continued for 1 week. Ulcer induction resulted in a significant increase in serum levels of VEGF and a significant decrease in serum levels of endostatin (an antiangiogenic factor). Although both aspirin and ticlopidine markedly suppressed platelet aggregation, only ticlopidine impaired gastric ulcer healing and angiogenesis as well as reversing the ulcerassociated changes in serum levels of VEGF and endostatin. The effects of ticlopidine on ulcer healing and angiogenesis were mimicked by immunodepletion of circulating platelets, and ticlopidine did not influence ulcer healing when given to thrombocytopenic rats. Incubation of human umbilical vein endothelial cells with serum from ticlopidine-treated rats significantly reduced proliferation and increased apoptosis, effects reversed by an antibody directed against endostatin. Ticlopidine treatment resulted in increased platelet endostatin content and release. These results demonstrate a previously unrecognized contribution of platelets to the regulation of gastric ulcer healing. Such effects likely are mediated through the release from platelets of endostatin and possibly VEGF. As shown with ticlopidine, drugs that influence gastric ulcer healing may do so in part through altering the ability of platelets to release growth factors.angiogenesis ͉ ticlopidine ͉ aspirin ͉ proliferation ͉ endothelium

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1 Selective inhibitors of cyclo-oxygenase-2 have been shown to be e ective anti-in¯ammatory drugs with reduced gastrointestinal toxicity relative to conventional nonsteroidal anti-in¯ammatory drugs (NSAIDs). In the present study, we examined the possibility that selective COX-2 inhibition, by blocking prostacyclin synthesis, would increase blood pressure and cause leukocyte adherence and platelet aggregation. 2 Normal rats and rats with hypertension induced by chronic administration of N o -nitro-Larginine methylester were given celecoxib (10 mg kg 71 ) daily for 3 weeks. Celecoxib signi®cantly elevated of blood pressure in both the normal and hypertensive rats (mean increase of 433 mm Hg after 3 weeks). 3 In normal rats, celecoxib had no e ect on serum 6-keto prostaglandin (PG)F 1a levels. Hypertensive rats exhibited a signi®cant increase (82%) in serum 6-keto PGF 1a levels, and this was reduced to the levels of normal rats by treatment with celecoxib. 4 Rats treated with celecoxib exhibited signi®cant increases in weight gain (20%), plasma argininevasopressin levels (148%) and plasma urea (69%) relative to vehicle-treated controls. Plasma creatinine levels were una ected by treatment with celecoxib, while plasma renin levels were signi®cantly decreased (30%) relative to controls. 5 Superfusion of mesenteric venules with celecoxib (3 mM) in vivo resulted in signi®cant increases in leukocyte adherence to the endothelium in both normal and hypertensive rats. 6 These studies suggest that suppression of COX-2 signi®cantly in¯uences vascular and/or renal function, leading to elevated blood pressure and leukocyte adherence.

The stomach is generally regarded as an environment that is not conducive to bacterial colonization. In this study, we examined the possibility that this changes significantly when an ulcer has formed and that colonization of ulcers interferes with the normal healing process. Gastric ulcers were induced by serosal application of acetic acid. The relationship between ulcer healing and bacterial colonization was examined. The effects of antibiotics, induction of Lactobacilluscolonization, and selective colonization with an antibiotic resistant strain of Escherichia coli on ulcer healing were examined. Within 6–12 h of their induction, gastric ulcers were colonized by a variety of bacteria, with gram-negative bacteria predominating. Suppression of colonization with antibiotics resulted in marked acceleration of healing. Induction of Lactobacillus colonization also accelerated ulcer healing. The beneficial effects of antibiotics were reversed through selective colonization with antibiotic-resistant E. coli. Bacterial colonization occurred irrespective of the method used to induce the ulcer. This study demonstrates that colonization of gastric ulcers in rats occurs rapidly and significantly impairs ulcer healing. This effect appeared to be primarily attributable to gram-negative bacteria.

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The acute antibody and T-cell immune response to Helicobacter pylori infection in humans has not been studied systematically. Serum from H. pylori-naive volunteers challenged with H. pylori and cured after 4 or 12 weeks was tested by enzyme-linked immunosorbent assays for anti-H. pylori-specific immunoglobulin M (IgM) and IgA established using bacterial lysates from homologous (the infecting strain) and heterologous H.

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There is an abundance of evidence that nitric oxide plays a critical role in regulating several components of gastrointestinal mucosal defense. Suppression of nitric oxide synthesis increases susceptibility to injury, while administration of nitric oxide donors increases resistance to injury. On the other hand, nitric oxide has been implicated as a mediator of tissue injury in the gastrointestinal tract during inflammatory reactions. In these cases, the nitric oxide is generally believed to be derived from an inducible isoform of nitric oxide synthase. In this review, we provide an overview of the evidence for and against these dual roles of nitric oxide in modulating gastrointestinal mucosal defense and injury. We also highlight the potential therapeutic benefits that may be realized through modulation of tissue nitric oxide levels.