PATHOPHYSIOLOGICAL ROLE OF NITRIC-OXIDE IN RAT EXPERIMENTAL COLITIS

Overproduction of nitric oxide (NO) by inducible nitric oxide synthase (iNOS) may contribute to the pathophysiology of ulcerative colitis. A 2,4,6-trinitrobenzenesulfonic acid sodium salt (TNBS) colitis model w as established to examine the effect of selective iNOS inhibition, by S-(2-aminoethyl) isothiouronium bromide (ITU), on colonic mucosal cell damage and inflammation. Rats, killed 7 days after TNBS, had increase d colonic mucosal levels of iNOS and interleukin-8 (IL-8), in addition to severe colonic inflammation which was characterized by significant ly increased colon weight, damage score and colonic myeloperoxidase ac tivity (MPO) (a marker of neutrophil influx). TNBS-treated rats had ma rkedly decreased body weight and thymus weight. Administration of coli tic rats with ITU significantly inhibited iNOS activity/expression and tended to reduce mucosal levels of IL-8, but no effect on MPO activit y was observed. Following ITU therapy, colitic rats had reduced coloni c damage and losses in body weight and thymus weight were reversed. Im provement of TNBS colitis by ITU suggested that excess NO; produced by iNOS, may have contributed to the initiation/amplification of colonic disease, by mechanisms including enhancement of IL-8 release. NO-medi ated enhancement of pro-inflammatory cytokine release was further inve stigated in vitro. Lipopolysaccharide (LPS) and interferon-gamma (IFN- gamma) stimulated release of nitrite, lactate dehydrogenase (LDH), TNF alpha, IL-1 beta and IL-8 from rat peritoneal macrophages, all of whi ch were significantly reduced by ITU. This suggests that NO-mediated c ell damage enhances pro-inflammatory mediator release from macrophages . In addition, enhancement of IL-8 and TNF alpha release was also part ially NO-dependent in activated peritoneal neutrophils. Therefore, the amelioration of TNBS colitis by ITU could include inhibition of NO-me diated pro-inflammatory cytokine release. (C) 1998 International Socie ty for Immunopharmacology.