Exacerbated Airway Toxicity of Environmental Oxidant Ozone in Mice Deficient in Nrf2

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 (Nrf2(-/-)) and wild-type (Nrf2(+/+)) 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 subacute O-3 exposures heightened pulmonary inflammation, edema, and cell death more severely in Nrf2(-/-) mice than in Nrf2(+/+) 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, bronchial mucous hypersecretion was greater in Nrf2(-/-) mice than in Nrf2(+/+) mice. Relative to Nrf2(+/+), O-3 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 O-3.