Exacerbated airway toxicity of environmental oxidant ozone in mice deficient in Nrf2

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