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Published ahead of print on December 4, 2008, doi:10.1165/rcmb.2008-0381OC

Am. J. Respir. Cell Mol. Biol., Volume 41, Number 1, July 2009, 107-113

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Submitted on October 8, 2008
Accepted on December 3, 2008

NAD(P)H Quinone Oxidoreductase 1 Is Essential for Ozone-induced Oxidative Stress in Mice and Humans

Judith A. Voynow1*, Bernard M Fischer1, Shuo Zheng1, Erin Potts2, Amy Grover1, Anil K. Jaiswal3, Andrew J. Ghio4, and W. Michael Foster5

1 Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, United States, 2 Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States, 3 Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland, United States, 4 Human Studies Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, United States, 5 Department of Medicine, Duke Unversity Medical Center, Durham, North Carolina, United States

* To whom correspondence should be addressed. E-mail: voyno001{at}mc.duke.edu.

One host susceptibility factor for ozone identified in epidemiologic studies is NAD(P)H quinone oxidoreductase 1 (NQO1). We hypothesized that following ozone exposure, NQO1 is required to increase 8-isoprostane (also known as F2-isoprostane) production, a recognized marker of ozone-induced oxidative stress, and to enhance airway inflammation and hyperresponsiveness. In this report, we demonstrate that in contrast to wild-type mice, NQO1-null mice are resistant to ozone and have blunted responses including decreased production of F2-isoprostane and keratinocyte chemokine, decreased airway inflammation, and diminished airway hyperreponsiveness. Importantly, these results in mice correlate with in vitro findings in humans. In primary human airway epithelial cells, inhibition of NQO1 by dicumarol, blocks ozone-induced F2-isoprostane production and IL-8 gene expression. Together, these results demonstrate that NQO1 modulates cellular redox status and influences the biologic and physiologic effects of ozone.
Key words: ozone • NAD(P)H quinone oxidoreductase 1 • F2-isoprostane




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