EXPRESSION OF INDUCIBLE NITRIC-OXIDE SYNTHASE AND NITROTYROSINE IN COLONIC EPITHELIUM IN INFLAMMATORY BOWEL-DISEASE

Background & Aims: Inducible nitric oxide synthase (iNOS) is generated in several cell types by treatment with lipopolysaccharides or cytoki nes. Earlier studies suggested that ulcerative colitis is associated w ith increased NO produced by iNOS; however, the cellular source of the NO synthesis was not identified. A possible mechanism of NO-induced c ellular damage is through its interaction with superoxide to produce p eroxynitrite, which reacts with tyrosine to form nitrotyrosine in cell ular proteins. Methods: Using immunoperoxidase microscopy with a new m onospecific human iNOS antibody (NO-53), the cellular distribution of iNOS and nitrotyrosine was examined using human colonic mucosa from no rmal bower, ulcerative colitis, Crohn's disease, and diverticulitis. R esults: Intense focal iNOS labeling was localized to the inflamed colo nic epithelium in ulcerative colitis, Crohn's disease, and diverticuli tis but was not detectable in the uninflamed epithelium. Nitrotyrosine labeling was also observed in the inflamed colonic epithelium and was associated with nearby iNOS staining; nitrotyrosine was undetectable in normal mucosal epithelium. iNOS and nitrotyrosine were also detecte d in lamina propria mononuclear cells and neutrophils. Conclusions: th ese findings suggest that iNOS is induced in the inflamed human coloni c epithelium and is associated with the formation of peroxynitrite and the nitration of cellular proteins.