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

B. Zingarelli, C. Szabo, A. L. Salzman

    Research output: Contribution to journalArticle

    126 Scopus citations

    Abstract

    Background and 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 upregulation, 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.

    Original languageEnglish (US)
    Pages (from-to)335-345
    Number of pages11
    JournalGastroenterology
    Volume116
    Issue number2
    DOIs
    StatePublished - Jan 1 1999

    ASJC Scopus subject areas

    • Hepatology
    • Gastroenterology

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