Department of Respiratory Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
Respir Res. 2010 Mar 18;11(1):31. doi: 10.1186/1465-9921-11-31.
Pulmonary fibrosis is a progressive and lethal disorder. Although the precise mechanisms of pulmonary fibrosis are not fully understood, oxidant/antioxidant and Th1/Th2 balances may play an important role in many of the processes of inflammation and fibrosis. The transcription factor Nrf2 acts as a critical regulator for various inflammatory and immune responses by controlling oxidative stress. We therefore investigated the protective role of Nrf2 against the development of pulmonary fibrosis.
To generate pulmonary fibrosis, both wild-type C57BL/6 mice and Nrf2-deficient mice of the same background were administered bleomycin intratracheally.
The survival of Nrf2-deficient mice after bleomycin administration was significantly lower than that of wild-type mice. The degree of bleomycin-induced initial pulmonary inflammation and pulmonary fibrosis was much more severe in Nrf2-deficient mice than in wild-type mice. The expression of antioxidant enzymes and phase II detoxifying enzymes was significantly reduced in the lungs of Nrf2-deficient mice, concomitant with an elevation of lung 8-isoprostane level, compared with wild-type mice. The expression of Th2 cytokines, such as interleukin-4 and interleukin-13, was significantly elevated in the lungs of Nrf2-deficient mice with an increase in the number of Th2 cells that express GATA-binding protein 3.
The results indicated that Nrf2 protects against the development of pulmonary fibrosis by regulating the cellular redox level and lung Th1/Th2 balance. Thus, Nrf2 might be an important genetic factor in the determination of susceptibility to pulmonary fibrosis.
肺纤维化是一种进行性和致命性疾病。尽管肺纤维化的确切机制尚未完全阐明，但氧化应激/抗氧化和 Th1/Th2 平衡可能在许多炎症和纤维化过程中发挥重要作用。转录因子 Nrf2 通过控制氧化应激，对各种炎症和免疫反应起着关键的调节作用。因此，我们研究了 Nrf2 对肺纤维化发展的保护作用。
为了产生肺纤维化，我们对同背景的野生型 C57BL/6 小鼠和 Nrf2 缺陷型小鼠经气管内给予博莱霉素。
博莱霉素给药后 Nrf2 缺陷型小鼠的存活率明显低于野生型小鼠。Nrf2 缺陷型小鼠博莱霉素诱导的初始肺炎症和肺纤维化的程度比野生型小鼠严重得多。Nrf2 缺陷型小鼠肺组织中抗氧化酶和 II 相解毒酶的表达明显降低，同时肺 8-异前列腺素水平升高，与野生型小鼠相比。Nrf2 缺陷型小鼠肺组织中 Th2 细胞因子（如白细胞介素-4 和白细胞介素-13）的表达明显升高，表达 GATA 结合蛋白 3 的 Th2 细胞数量增加。
这些结果表明，Nrf2 通过调节细胞氧化还原水平和肺 Th1/Th2 平衡来防止肺纤维化的发展。因此，Nrf2 可能是决定肺纤维化易感性的一个重要遗传因素。
