The protective role of Nrf2 in the development of acute lung injury and pulmonary fibrosis

氧化应激可能在急性肺损伤和肺纤维化的发病机制中起重要作用。转录因子Nrf2通过抗氧化剂反应元件(ARE)转录激活来对抗氧化组织损伤和炎症。为了阐明Nrf2在急性肺损伤和肺纤维化发生发展中的保护作用，用博莱霉素对C57BL/6野生型(WT)小鼠和Nrf2基因敲除(Nrf2-/-)小鼠进行了研究。与WT小鼠相比，Nrf2-/-小鼠博莱霉素治疗后的存活率显著降低。给药后第1天和第3天，Nrf2-/-小鼠的急性肺损伤程度明显高于WT小鼠。给药28天后，Nrf2-/-小鼠的肺纤维化程度也比WT小鼠严重得多。给药后WT小鼠肺组织中可诱导抗氧化剂和2相酶的表达，而Nrf2-/-小鼠肺组织中不能诱导表达。结果表明，Nrf2通过调节抗氧化剂分子的表达来降低氧化应激，从而对急性肺损伤和肺纤维化的发展具有保护作用。

Oxidative stress may play an important role in the pthogenesis of acute lung injury and pulmonary fibrosis. Transcription factor Nrf2 counteracts oxidative tissue damage and inflammation through transcriptional activation via the antioxidant responsive element (ARE). To clarify the protective role of Nrf2 in the development of acute lung injury and pulmonary fibrosis, bleomycin was administrated to both C57BL/6 wild-type (WT) mice and Nrf2-knockout (Nrf2-/-) mice of the same background. The survival rate after bleomycin treatment was significantly decreased in Nrf2-/-mice compared with WT mice. The degree of acute lung injury, indicated by albumin concentration and the number of neutrophils in bronchoalveolar fluids, was much higher in Nrf2-/-mice than in WT mice 1 and 3 days after bleomycin administration. The degree of pulmonary fibrosis was also much greater in Nrf2-/-mice than in WT mice 28 days after bleomycin administration. The expression of antioxidant and phase 2 enzymes was inducible in the lungs of WT mice, but not in that of Nrf2-/- mice after bleomycin administration. Results indicated that Nrf2 protects against the development of acute lung injury and pulmonary fibrosis by lowering oxidative stress through regulating the expression of antioxidant molecules.