Exacerbated Airway Toxicity of Environmental Oxidant Ozone in Mice Deficient inNrf2

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 O3in 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 O3exposures heightened pulmonary inflammation, edema, and cell death more severely inNrf2-/-mice than inNrf2+/+mice. O3caused 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 inNrf2-/-mice than inNrf2+/+mice. Relative toNrf2+/+, O3augmented lung protein and lipid oxidation more highly inNrf2-/-mice. Results suggest thatNrf2deficiency exacerbates oxidative stress and airway injury caused by the environmental pollutant O3.