关键词: Nrf2/ARE信号通路, 运动预适应, 低压低氧, 大鼠, 肺损伤, 保护作用

Abstract: BACKGROUND: Hypobaric hypoxia can affect the lung function of rats, triggering cell apoptosis in lung tissue and inducing pulmonary vascular remodeling. Exercise preconditioning can relieve lung injury caused by pulmonary vascular remodeling by up-regulating the nuclear factor E2- related factor 2 (Nrf2)/antioxidant response element (ARE) pathway in lung tissue.
OBJECTIVE: To explore the protective effect of exercise preconditioning on lung injury induced by hypobaric hypoxia in rats based on the Nrf2/ARE signal pathway. 
METHODS: Eighty Sprague-Dawley rats were randomly divided into four groups with 20 rats in each group: normal group, model group, short-term exercise precondition group (short-term group) and long-term exercise preconditioning group (long-term group). The short-term group was required to swimming training for 1 continuous week, while the long-term group was required to exercise for 3 weeks same as the short-term group. On the next day after the last exercise preconditioning, the rats in the short- and long-term groups were slowly and uniformly decompressed to 8 000 meters above sea level (rising at a speed of 10 m/s) in a hypobaric chamber, and underwent continuous hypoxia for 48 hours, during which the rats in the normal group were given any treatment. Pathological changes of the lung tissue was observed by hematoxylin-eosin staining, pulmonary vascular remodeling was observed by elastic van gieson staining, apoptosis in pulmonary artery smooth muscle cells was detected by TUNEL staining, and vascular endothelial growth factor and α-smooth muscle actin in pulmonary artery tissue were detected by immunohistochemistry. The expression of reactive oxygen species in blood, activities of superoxide dismutase activity, glutathione peroxidase and catalase in lung tissue were detected by reactive oxygen species kit, xanthine oxidase method, dithiodinitrobenzoic acid and ammonium molybdate chemical colorimetric method, respectively. Nrf2/ARE signaling pathway protein in rat lung tissue was detected using western blot assay. Respiratory frequency, tidal volume and ventilation per minute in each rat were recorded. 
RESULTS AND CONCLUSION: Compared with the normal group, in the model group, the respiratory frequency was significantly increased, the tidal volume and minute ventilation were significantly decreased, the medial thickness of pulmonary arterioles and the degree of vascular muscularization were significantly increased, the apoptosis rate, the expression of α-smooth muscle actin and vascular endothelial growth factor, reactive oxygen species level and the expression of Nrf2 and ARE were significantly increased, and the activities of superoxide dismutase activity, glutathione peroxidase and catalase were significantly decreased. Compared with the model group, in both short- and long-term groups, the respiratory frequency was significantly lowered, the tidal volume and ventilation per minute were significantly increased, the medial thickness and the degree of vascular muscularization in the lung tissue were significantly reduced, the apoptosis rate, α-smooth muscle actin and vascular endothelial growth factor expression, reactive oxygen species level and the expression of Nrf2 and ARE were significantly decreased, and the activities of superoxide dismutase activity, glutathione peroxidase and catalase were significantly increased (P < 0.05). These changes were more obvious in the long-term group than the short-term group. To conclude, hypobaric hypoxia can affect lung function and cause lung tissue injury, exercise preconditioning can enhance the activities of superoxide dismutase activity, glutathione peroxidase and catalase, decrease the level of reactive oxygen species and the expression of α-smooth muscle actin and vascular endothelial growth factor by up-regulating Nrf2/ARE pathway in lung tissue, so as to improve the antioxidant capacity of lung tissue, reduce the apoptosis rate of lung tissue and improve the symptoms of pulmonary vascular remodeling, thus improving lung injury induced by hypobaric hypoxia. And long-term exercise preconditioning is superior to short-term exercise preconditioning in protecting lung tissue.

Key words: Nrf2/ARE signal pathway, exercise preconditioning, hypobaric hypoxia, rat, lung injury, protective effect