The potential role of nitric oxide in chronic inflammatory bowel disorders

The aetiology of the chronic inflammatory bowel diseases-ulcerative colitis and Crohn's disease-as well as 'microscopic colitis'-both collagenous (COC ) and lymphocytic colitis (LC)-remains unknown. Autoimmune mechanisms, cyto kine polymorphism, commensal bacteria, infectious agents and vascular impai rment have all been proposed as playing important roles in the pathogenesis of this spectrum of diseases. A variety of proinflammatory mediators, including tumour necrosis factor al pha, interleukin-1 beta, interferon gamma, leukotriene B-4 and platelet act ivating factor, promote the adherence of phagocytes to the venular endothel ium and extravasation of these cells into the colonic mucosa. In addition t o large amounts of nitric oxide (NO), injurious peroxynitrite may be formed in the epithelium by the inducible nitric oxide synthase (iNOS), which is considered to elicit cytotoxicity by the generation of superoxide with redu ced L-arginine availability. In active ulcerative colitis, and to a lesser extent in Crohn's disease, a greatly increased production of NO has been de monstrated by indirect and direct measurements. Surprisingly, even higher r ates of production have been observed in COC-a condition which is never ass ociated with injurious inflammation, The latter observation favours the not ion that NO promotes mucosal integrity. Further evidence for a protective r ole of NO in chronic inflammatory bowel disorders is provided by the observ ation of increased susceptibility to the induction of experimental colitis in 'knock-out' mice deficient in iNOS, Selective inhibitors of iNOS activity, as well as topical L-arginine, may t herefore prove beneficial in inflammatory bowel disease by reducing the pro duction of superoxide by iNOS, while only the former option may be expected to reduce diarrhoea in chronic inflammatory bowel disorders. Clearly, furt her experimental work needs to be done before testing topical L-arginine in human inflammatory bowel disease.