Introduction: Inflammatory bowel disease is characterized by oxidative and nitrosative stress, leukocyte infiltration, and upregulation of intercellular adhesion molecule-1 (ICAM-1) expression in the colon. Recent data demonstrate that oxidative and nitrosative stress in isolated enterocytes produces DNA single-strand breaks which 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 genetically deficient of PARS (PARS-/-) and in wild-type littermates. Survival and signs of illness and colonic inflammation were monitored for 7 days. Results: PARS+/+ mice appeared markedly more sensitive to the injurious effects of TNBS: all developed bloody diarrhea and mortality occurred early and was substantial (50% and 78% died within 2 and 6 days, respectively, after TNBS administration). In contrast, only 20% of PARS-/- mice exhibited a serious diarrhea and died within 48 hours. The surviving mice appeared healthy and exhibited a very mild diarrhea. Weight loss was also more pronounced in wild-type than in PARS-/- mice. In wild-type mice TNBS treatment resulted in colonic erosion and ulceration, which was maintained up to 7 days. Neutrophil infiltration (indicated by myeloperoxidase activity in the mucosa) was associated with upregulation of ICAM-1, high levels of malondialdehyde and nitrotyrosine. TNBS-treated PARS-/- mice experienced a similar colonic injury, which was, however, completely resolved by 6 days. Resolution of the damage was associated with absence of ICAM-1 upregulation, reduction of neutrophil infiltration, lipid peroxidation, and nitrosative damage. Conclusions: These data demonstrate that PARS plays a critical role in colonic inflammation possibly by regulating ICAM-1 expression, neutrophil recruitment, and the subsequent oxidant generation. Inhibition of PARS interrupts this positive feedback cycle, and may represent a novel therapeutic approach to the treatment of colitis.
ASJC Scopus subject areas
- Critical Care and Intensive Care Medicine