Exacerbated Airway Toxicity of Environmental Oxidant Ozone in Mice Deficient inNrf2

Ozone (O 3 ) 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 O 3 in mice. For this purpose, Nrf2 -deficient ( Nrf 2 −/− ) and wild-type ( Nrf 2 +/+ ) mice received acute and subacute exposures to O 3 . 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 O 3 exposures heightened pulmonary inflammation, edema, and cell death more severely in Nrf 2 −/− mice than in Nrf 2 +/+ mice. O 3 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 Nrf 2 −/− mice than in Nrf 2 +/+ mice. Relative to Nrf 2 +/+ , O 3 augmented lung protein and lipid oxidation more highly in Nrf 2 −/− mice. Results suggest that Nrf2 deficiency exacerbates oxidative stress and airway injury caused by the environmental pollutant O 3 .