title: Gene knockout or pharmacological inhibition of poly(ADP-ribose) polymerase-1 prevents lung inflammation in a murine model of asthma.
abstract: 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. H(2)O(2) 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-kappaB and expression of the interleukin-8 gene induced by H(2)O(2) 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Lung Laboratory, Georgetown University School of Medicine, Washington, District of Columbia, USA. hboulr@lsuhsc.edu
authors.forename: A Hamid
authors.initials: AH
authors.lastname: Boulares
authors.forename: Anna J
authors.initials: AJ
authors.lastname: Zoltoski
authors.forename: Zaki A
authors.initials: ZA
authors.lastname: Sherif
authors.forename: Puneet
authors.initials: P
authors.lastname: Jolly
authors.forename: Donald
authors.initials: D
authors.lastname: Massaro
authors.forename: Mark E
authors.initials: ME
authors.lastname: Smulson
mesh_terms: D000485:Allergens / Q000008:administration & dosage / Q000276:immunology; D000818:Animals; D001249:Asthma / Q000517:prevention & control*; D001549:Benzamides / Q000494:pharmacology; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced / Q000517:prevention & control; D016209:Interleukin-8 / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008168:Lung / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D016877:Oxidants / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D000485:Allergens; D001549:Benzamides; D004791:Enzyme Inhibitors; D016209:Interleukin-8; D016328:NF-kappa B; D016877:Oxidants; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C025160:3-aminobenzamide; D010047:Ovalbumin; D006861:Hydrogen Peroxide; D007770:L-Lactate Dehydrogenase; D019001:Nitric Oxide Synthase; D011065:Poly(ADP-ribose) Polymerases