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American Journal of Respiratory Cell and Molecular Biology. Vol. 28, pp. 322-329, 2003
© 2003 American Thoracic Society
DOI: 10.1165/rcmb.2001-0015OC

Gene Knockout or Pharmacological Inhibition of Poly(ADP-Ribose) Polymerase-1 Prevents Lung Inflammation in a Murine Model of Asthma

A. Hamid Boulares, Anna J. Zoltoski, Zaki A. Sherif, Puneet Jolly, Donald Massaro and Mark E. Smulson

Department of Biochemistry and Molecular Biology and Department of Medicine, Lung Laboratory, Georgetown University School of Medicine, Washington, District of Columbia

Address correspondence to: Hamid Boulares, Ph.D., Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, 1901 Perdido St., Room 5226, New Orleans, LA 70112. E-mail: hboulr{at}lsuhsc.edu

Airway inflammation is a central feature of asthma and chronic obstructive pulmonary disease. Reactive oxygen species (ROS) contribute to inflammation by damaging DNA, which, in turn, results in the activation of poly(ADP-ribose) polymerase-1 (PARP-1) and depletion of its substrate, nicotinamide adenine dinucleotide. Here we show that prevention of PARP-1 activation protects against both ROS-induced airway epithelial cell injury in vitro and airway inflammation in vivo. H2O2 induced the generation of ROS, PARP-1 activation and concomitant nicotinamide adenine dinucleotide depletion, and release of lactate dehydrogenase in A549 human airway epithelial cells. These effects were blocked by the PARP-1 inhibitor 3-aminobenzamide (3-AB). Furthermore, 3-AB inhibited both activation of the proinflammatory transcription factor nuclear factor-{kappa}B and expression of the interleukin-8 gene induced by H2O2 in these cells. In a murine model of allergen-induced asthma, 3-AB prevented airway inflammation elicited by ovalbumin. Moreover, PARP-1 knockout mice were resistant to such ovalbumin-induced inflammation. These protective effects were associated with an inhibition of expression of the inducible nitric oxide synthase. These results implicate PARP-1 activation in airway inflammation, and suggest this enzyme as a potential target for the development of new therapeutic strategies in the treatment of asthma as well as other respiratory disorders such as chronic obstructive pulmonary disease.

Abbreviations: 3-aminobenzamide, 3-AB • bronchoalveolar lavage, BAL • chronic obstructive pulmonary disease, COPD • electrophoretic mobility shift assay, EMSA • dihydrodichlorofluorescein, H2DCF • interleukin, IL • inducible NOS, iNOS • lactate dehydrogenase, LDH • N-acetyl cysteine, NAC • nuclear factor-{kappa}B, NF-{kappa}B • nitric oxide synthase, NOS • ovalbumin, OVA • poly(ADP-ribose), PAR • PAR polymerase-1, PARP-1 • phosphate-buffered saline, PBS • reactive oxygen species, ROS • tumor necrosis factor, TNF




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