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

Liaudet, L., Pacher, P., Mabley, J.G., Virag, L., Soriano, F.G., Hasko, G. and Szabo, C. (2002) Activation of poly(ADP-Ribose) polymerase-1 is a central mechanism of lipopolysaccharide-induced acute lung inflammation American Journal of Respiratory and Critical Care Medicine, 165 (3). pp. 372-377. ISSN 1073-449X

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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.

Item Type: Journal article
Uncontrolled Keywords: lung; ARDS; lipopolysaccharide; poly(ADP-ribose) polymerase; chemokines
Subjects: C000 Biological and Biomedical Sciences > C700 Molecular Biology, Biophysics and Biochemistry
DOI (a stable link to the resource): 10.1164/ajrccm.165.3.2106050
Faculties: Faculty of Science and Engineering > School of Pharmacy and Biomolecular Sciences > Chemical Biology
Depositing User: editor spbs
Date Deposited: 15 Nov 2006
Last Modified: 16 Apr 2014 15:39
URI: http://eprints.brighton.ac.uk/id/eprint/196

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