Poly (ADP) ribose synthetase inhibition in alveolar macrophages undergoing hypoxia and reoxygenation

Anton S. McCourtie, Alexander S. Farivar, Steven M. Woolley, Heather E. Merry, Patrick S. Wolf, Csaba Szabo, Michael S. Mulligan

    Research output: Contribution to journalArticlepeer-review

    9 Scopus citations


    Background: Inhibition of the nuclear enzyme poly ribose synthetase (PARS) protects against in vivo lung ischemia reperfusion injury (LIRI). The effectiveness of intratracheal treatment suggests that PARS inhibition may primarily modulate alveolar macrophage (AM) activation. These studies attempted to characterize the effects of PARS on AM activation in response to oxidative stress. Methods: Primary cultures of AM were rendered hypoxic for 2 h and reoxygenated for up to 4 h. Cells were preincubated with INO-1001, a specific PARS inhibitor 1 h prior to hypoxia. Gel shift assays characterized nuclear factor kappa B (NFκB), and enzyme linked immunosorbent assay quantitated chemokine/cytokine protein secretion. Results: Hypoxia and reoxygenation resulted in an increase in the early nuclear translocation of NFκB, and an increase in the secretion of the cytokine tumor necrosis factor-alpha (TNF-α), chemokines macrophage inflammatory protein (MIP-1α), monocyte chemoattractant protein one (MCP-1) and cytokine induced neutrophil chemoattractant (CINC). Pretreatment of AM with INO-1001 decreased both the early translocation of NFκB and the production of TNF-α (p < 0.05) and MIP-1α p = 0.02, but did not affect CINC or MCP-1 production. Conclusions: These findings indicate that PARS inhibition in the AM blunts their response to oxidative stress and may help explain the protective effects of intratracheal PARS inhibition in LIRI.

    Original languageEnglish (US)
    Pages (from-to)141-144
    Number of pages4
    JournalExperimental and Molecular Pathology
    Issue number2
    StatePublished - Apr 2008


    • Alveolar macrophage
    • Chemokines
    • Hypoxia
    • In vitro
    • Lung ischemia reperfusion injury cytokines
    • PARS
    • Reoxygenation

    ASJC Scopus subject areas

    • Pathology and Forensic Medicine
    • Molecular Biology
    • Clinical Biochemistry


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