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

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

Correspondence and requests for reprints should be addressed to Judith A. Voynow, M.D., Division of Pediatric Pulmonary Medicine, Department of Pediatrics, Duke University Medical Center, Box 2994, Durham, NC 27710. 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 after 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

CLINICAL RELEVANCE This study demonstrates in vitro and in vivo that NAD(P)H quinone oxidoreductase 1 is a host susceptibility factor that confers oxidative stress, inflammation, and airway obstruction after ozone exposure in mice. To our knowledge, this is the first demonstration relating a cellular redox pathway with a candidate host susceptibility gene that has been previously identified in epidemiologic investigations of asthma risk.

 

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