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

L. Liaudet, P. Pacher, Jon Mabley, L. Virag, F.G. Soriano, G. Hasko, C. Szabo

Research output: Contribution to journalArticle

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-alpha , IL-1beta , and IL-6, the chemokines MIP-1alpha 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
Pages (from-to)372-377
Number of pages6
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume165
Issue number3
DOIs
Publication statusPublished - Feb 2002

Keywords

  • lung
  • ARDS
  • lipopolysaccharide
  • poly(ADP-ribose) polymerase
  • chemokines

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