NAD(P)H quinone oxidoreductase 1 is essential for ozone-induced oxidative stress in mice and humans.
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.
Voynow
Judith A
JA
Division of Pediatric Pulmonary Medicine, Department of Pediatrics, Duke University Medical Center, Box 2994, Durham, NC 27710, USA. voyno001@mc.duke.edu
Fischer
Bernard M
BM
Zheng
Shuo
S
Potts
Erin N
EN
Grover
Amy R
AR
Jaiswal
Anil K
AK
Ghio
Andrew J
AJ
Foster
W Michael
WM
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
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