title: Exacerbated airway toxicity of environmental oxidant ozone in mice deficient in Nrf2.
abstract: Ozone (O3) is a strong oxidant in air pollution that has harmful effects on airways and exacerbates respiratory disorders. The transcription factor Nrf2 protects airways from oxidative stress through antioxidant response element-bearing defense gene induction. The present study was designed to determine the role of Nrf2 in airway toxicity caused by inhaled O3 in mice. For this purpose, Nrf2-deficient (Nrf2(-/-)) and wild-type (Nrf2(+/+)) mice received acute and subacute exposures to O3. Lung injury was determined by bronchoalveolar lavage and histopathologic analyses. Oxidation markers and mucus hypersecretion were determined by ELISA, and Nrf2 and its downstream effectors were determined by RT-PCR and/or Western blotting. Acute and sub-acute O3 exposures heightened pulmonary inflammation, edema, and cell death more severely in Nrf2(-/-) mice than in Nrf2(+/+) mice. O3 caused bronchiolar and terminal bronchiolar proliferation in both genotypes of mice, while the intensity of compensatory epithelial proliferation, bronchial mucous cell hyperplasia, and mucus hypersecretion was greater in Nrf2(-/-) mice than in Nrf2(+/+) mice. Relative to Nrf2(+/+), O3 augmented lung protein and lipid oxidation more highly in Nrf2(-/-) mice. Results suggest that Nrf2 deficiency exacerbates oxidative stress and airway injury caused by the environmental pollutant O3.
authors.affiliation: Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA. cho2@niehs.nih.gov
authors.forename: Hye-Youn
authors.initials: HY
authors.lastname: Cho
authors.forename: Wesley
authors.initials: W
authors.lastname: Gladwell
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Steven R
authors.initials: SR
authors.lastname: Kleeberger
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid; D018450:Disease Progression; D004781:Environmental Exposure; D008168:Lung / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D009093:Mucus / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D016877:Oxidants / Q000633:toxicity*; D010084:Oxidation-Reduction / Q000187:drug effects; D010126:Ozone / Q000633:toxicity*
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D016877:Oxidants; D010126:Ozone