Peroxynitrite-induced rat colitis--a new model of colonic inflammation.
BACKGROUND: Excessive production of nitric oxide, characteristic of inflamed states, may have deleterious effects through its facile conversion (in the presence of O2) to peroxynitrite, which promotes lipid and sulfhydryl oxidation. This study assessed the effect of peroxynitrite on the rat colon. METHODS: Peroxynitrite was administered intrarectally to rats. One, 3, 7, and 21 days after treatment, a distal colonic segment was isolated and tissue was obtained for histological evaluation and determination of myeloperoxidase activity and NOX, and eicosanoids generation. RESULTS: Within 24 hours, the exposed segment was edematous and congested with occasional hemorrhagic mucosal ulceration. On day 7, the lumen was narrow; at day 21, there were signs of stenosis. Histological analysis showed transmucosal necrosis, acute inflammation, and exudative edema 24 hours after treatment. Surface re-epithelization and infiltration of granulation tissue were present at 1 week. Resolution of edema, mucin repletion, thickening of muscularis mucosa and propria, and fibrosis were observed at 3 weeks. Significant increase in NOX generation and myeloperoxidase and NO synthase activities were observed at 24 hours, whereas enhanced leukotriene generation was observed only at 21 days. CONCLUSIONS: Peroxynitrite-induced colonic inflammation provides a novel model of NO-related tissue injury and offers the opportunity to further explore the potential role of NO in the pathogenesis of inflammatory bowel disease.
Rachmilewitz, D; Stamler, JS; Karmeli, F; Mullins, ME; Singel, DJ; Loscalzo, J; Xavier, RJ; Podolsky, DK
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