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

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-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-B, NF-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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