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过程中起重要作用。转录因子Nrf2通过抗氧化反应元件（ARE）的转录激活来抵消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中的保护作用，我们在相同背景下对C57BL/6野生型（WT）小鼠和Nrf2敲除（Nrf2-/-）小鼠给予博来霉素。与WT小鼠相比，Nrf2-/-小鼠博来霉素治疗后存活率显著降低。在给予博来霉素1和3天后，Nrf2-/-小鼠的急性肺损伤程度（以支气管肺泡液白蛋白浓度和中性粒细胞数量为指标）明显高于WT小鼠。给予博来霉素28天后，Nrf2-/-小鼠的肺纤维化程度也比WT小鼠大得多。博莱霉素可诱导WT小鼠肺组织中抗氧化酶和2相酶的表达，但不能诱导Nrf2-/-小鼠肺组织中抗氧化酶和2相酶的表达。结果表明，Nrf2通过调节抗氧化分子的表达，降低氧化应激，对急性肺损伤和肺纤维化的发生具有保护作用。

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.