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Am. J. Respir. Crit. Care Med., Volume 165, Number 3, February 2002, 372-377

Activation of Poly(ADP-Ribose) Polymerase-1 Is a Central Mechanism of Lipopolysaccharide-Induced Acute Lung Inflammation

LUCAS LIAUDET, PÁL PACHER, JON G. MABLEY, LÁSZLÓ VIRÁG, FRANCISCO G. SORIANO, GYÖRGY HASKÓ, and CSABA SZABÓ

Inotek Corporation, Beverly, Massachusetts; and Department of Surgery, New Jersey Medical School, UMDNJ, Newark, New Jersey

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.




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Copyright © 2002 American Thoracic Society 		  Registrer for the conference