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Cyclo‐oxygenase‐2 inhibitors ameliorate the severity of experimental colitis in rats

Background Both in experimental colitis and in inflammatory bowel disease, colonic eicosanoid generation is enhanced and may contribute to the pathogenesis of the inflammatory response. Aims To evaluate the effect of selective cyclo‐oxygenase‐2 (COX‐2) inhibitors on the extent and severity of two models of experimental colitis. Methods Colitis was induced by intra‐caecal administration of 2 ml 5% acetic acid or intra‐colonic administration of 0.1 ml 3% iodoacetamide. Rats were treated intra‐gastrically with nimesulide 2 × 10 mg/kg/day, or once with SC‐236 6 mg/kg, and killed 1 or 3 days after damage induction. The colon was isolated, weighed, macroscopic damage was measured, and mucosal samples were obtained for histology and for determination of myeloperoxidase (MPO) and nitric oxide synthase (NOS) activities and eicosanoid generation. The serum levels of thromboxane B2 (TXB2), tumour necrosis factor‐&agr; (TNF‐&agr;) and interleukin‐1&bgr; (IL‐1&bgr;) were determined. Results Nimesulide significantly decreased the extent of colitis induced by acetic acid. Both nimesulide and SC‐236 significantly decreased the extent of iodoacetamideinduced colonic damage. The decrease in the extent of colitis induced by nimesulide was accompanied by a significant decrease in mucosal MPO and NOS activities. Nimesulide and SC‐236 decreased the enhanced colonic eicosanoid generation in acetic acid and iodoacetamideinduced colitis, and, in iodoacetamide‐treated rats, nimesulide also decreased the elevated serum TNF‐&agr; and IL‐1&bgr; levels. Conclusions The effective nimesulide and SC‐236‐induced amelioration of the severity of the colitis in acetic acid and iodoacetamide‐treated rats confirms the role of eicosanoids in their pathogenesis and suggests that COX‐2 inhibitors may be of value in the treatment of inflammatory bowel disease. Eur J Gastroenterol Hepatol 12:223‐231 © 2000 Lippincott Williams & Wilkins European Journal of Gastroenterology & Hepatology 2000, 12:223‐231