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.
Highlights
Ozone (O3) is a highly reactive gaseous oxidant air pollutant
Overall, compared to acute O3 exposure, sub-acute O3 exposure caused greater pulmonary protein edema determined by total protein concentration and airway cell lysis determined by lactate dehydrogenase level by 72 hr exposure
Relative to Nrf2+/+ mice, significantly heightened lung cell cytotoxicity indicated by Bronchoalveolar Lavage (BAL) lactate dehydrogenase level, edema indicated by total BAL protein concentration, and epithelial exfoliation were found in Nrf2−/− mice (Figure 1)
Summary
Ozone (O3) is a highly reactive gaseous oxidant air pollutant. Elevated levels of ambient O3 have been associated with increased hospital visits and respiratory symptoms including chest discomfort, breathing difficulties, coughing, and lung function decrement [1, 2]. Controlled O3 exposure studies in healthy volunteers found oxidant generation and temporal antioxidant depletion in fluid lining compartments of the airways or sputum [4]. Inhaled O3 in experimental animal models causes airway inflammation and hyperresponsiveness, reactive oxygen species (ROS) production, mucus overproduction, and epithelial damage and compensatory proliferation predominantly in ciliated cells of the upper respiratory tract and Clara cells in terminal bronchioles. Long-term exposure of O3 may cause lung tumors in certain strains of mice [5]
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