BLOCKADE OF POLY (ADP-RIBOSE) SYNTHETASE INHIBITS NEUTROPHIL RECRUITMENT, OXIDANT GENERATION, AND MUCOSAL INJURY IN MURINE COLITIS

Abstract

Abstract Background & Aims: Inflammatory bowel disease is characterized by oxidative and nitrosative stress, leukocyte infiltration, and up-regulation of intercellular adhesion molecule 1 (ICAM-1) expression in the colon. Recent data show that oxidative and nitrosative stress in isolated enterocytes produces DNA single-strand breaks that activate the nuclear enzyme poly(ADP-ribose) synthetase (PARS), resulting in depletion of intracellular energetics and increased paracellular permeability. The aim of the present study was to examine the in vivo relevance of this injury pathway. Methods: Colitis was induced by rectal instillation of trinitrobenzenesulfonic acid (TNBS) in mice with a genetic deficiency of PARS (PARS −/− ) and in wild-type littermates. Results: In wild-type mice, TNBS treatment resulted in colonic erosion and ulceration that was maintained up to 7 days. Neutrophil infiltration (indicated by myeloperoxidase activity in the mucosa) was associated with up-regulation of ICAM-1 and high levels of malondialdehyde and nitrotyrosine. TNBS-treated PARS −/− mice experienced a similar colonic injury that was, however, completely resolved by 6 days. Resolution of the damage was associated with absence of ICAM-1 up-regulation, reduction of neutrophil infiltration, lipid peroxidation, and nitrosative damage. Conclusions: These data show that PARS plays a critical role in colonic inflammation possibly by regulating ICAM-1 expression, neutrophil recruitment, and the subsequent oxidant generation. GASTROENTEROLOGY 1999;116:335-345