title: NAD(P)H quinone oxidoreductase 1 is essential for ozone-induced oxidative stress in mice and humans.
abstract: 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 F(2)-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 F(2)-isoprostane and keratinocyte chemokine, decreased airway inflammation, and diminished airway hyperresponsiveness. 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 F(2)-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.
authors.affiliation: Division of Pediatric Pulmonary Medicine, Department of Pediatrics, Duke University Medical Center, Box 2994, Durham, NC 27710, USA. voyno001@mc.duke.edu
authors.forename: Judith A
authors.initials: JA
authors.lastname: Voynow
authors.forename: Bernard M
authors.initials: BM
authors.lastname: Fischer
authors.forename: Shuo
authors.initials: S
authors.lastname: Zheng
authors.forename: Erin N
authors.initials: EN
authors.lastname: Potts
authors.forename: Amy R
authors.initials: AR
authors.lastname: Grover
authors.forename: Anil K
authors.initials: AK
authors.lastname: Jaiswal
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Ghio
authors.forename: W Michael
authors.initials: WM
authors.lastname: Foster
mesh_terms: D000818:Animals; D001980:Bronchi / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology / Q000517:prevention & control; D001985:Bronchial Provocation Tests; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D001728:Dicumarol / Q000494:pharmacology; D015237:Dinoprost / Q000031:analogs & derivatives / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016660:NAD(P)H Dehydrogenase (Quinone); D009252:NADPH Dehydrogenase / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016877:Oxidants / Q000633:toxicity*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D010126:Ozone / Q000633:toxicity*; D011014:Pneumonia / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology / Q000517:prevention & control; D013997:Time Factors
chemical_list: C508606:CXCL8 protein, human; D018925:Chemokines; D004791:Enzyme Inhibitors; D016209:Interleukin-8; D016877:Oxidants; C074302:keratinocyte-derived chemokines; C075750:8-epi-prostaglandin F2alpha; D010126:Ozone; D001728:Dicumarol; D015237:Dinoprost; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse; D009252:NADPH Dehydrogenase