Activation of poly(ADP-ribose) polymerase-1 is a central mechanism of lipopolysaccharide-induced acute lung inflammation

Lucas Liaudet, P. Á L. Pacher, Jon G. Mabley, László Virág, Francisco G. Soriano, György Haskó, Csaba Szabó

    Research output: Contribution to journalArticle

    159 Scopus citations

    Abstract

    Recent studies demonstrated that activation of the nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1) by oxidant-mediated DNA damage is an important pathway of tissue injury in conditions associated with oxidative stress. Using a dual approach of PARP-1 suppression, by genetic deletion or pharmacological inhibition with the phenanthridinone PARP inhibitor PJ-34, we now demonstrate an essential role of PARP-1 in the development of pulmonary inflammation induced by lipopolysaccharide (LPS). PARP-1+/+ and PARP-1-/- mice received an intratracheal instillation of LPS (50 μg), followed after 24 h by bronchoalveolar lavage to measure the cytokines TNF-α, IL-1β, and IL-6, the chemokines MIP-1α and MIP-2, leukocyte counts and myeloperoxidase activity (neutrophil accumulation), protein content (high permeability edema), and nitrite/nitrate (nitric oxide production). Malondialdehyde (an index of lipid peroxidation) was measured in lung tissue. Similar experiments were conducted in BALB/c mice treated with PJ-34 or vehicle. The absence of functional PARP-1 reduced LPS-induced increases of cytokines and chemokines, alveolar neutrophil accumulation, lung hyperpermeability, NO production, and lipid peroxidation. Histological analysis revealed attenuated lung damage after PARP inhibition. Our findings support a mechanistic role of PARP-1 in the regulation of LPS-induced lung inflammation. Pharmacological inhibition of PARP may be useful in clinical conditions associated with overwhelming lung inflammation.

    Original languageEnglish (US)
    Pages (from-to)372-377
    Number of pages6
    JournalAmerican Journal of Respiratory and Critical Care Medicine
    Volume165
    Issue number3
    DOIs
    StatePublished - Feb 1 2002

    Keywords

    • ARDS
    • Chemokines
    • Lipopolysaccharide
    • Lung
    • Poly(ADP-ribose) polymerase

    ASJC Scopus subject areas

    • Pulmonary and Respiratory Medicine
    • Critical Care and Intensive Care Medicine

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