Blockade of poly(ADP-ribose) synthetase inhibits neutrophil recruitment, oxidant generation, and mucosal injury in murine colitis

Background & Aims: Inflammatory bowel disease is characterized by oxidative and nitrosative stress, leukocyte infiltration, and up-regulation of inter cellular 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 ex amine the in vivo relevance of this injury pathway. Methods: Colitis was in duced 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 (indic ated by myeloperoxidase activity in the mucosa) was associated with up-regu lation of ICAM-1 and high levels of malondialdehyde and nitrotyrosine. TNBS -treated PARS-/- mice experienced a similar colonic injury that was, howeve r, completely resolved by 6 days. Resolution of the damage was associated w ith absence of ICAM-1 upregulation, reduction of neutrophil infiltration, l ipid peroxidation, and nitrosative damage. Conclusions: These data show tha t PARS plays a critical role in colonic inflammation possibly by regulating ICAM-1 expression, neutrophil recruitment, and the subsequent oxidant gene ration.