ACE-AngⅡ-AT1受体轴/ACE2-Ang（1-7）-Mas轴对吸烟诱发氧化/抗氧化反应失衡导致的肺纤维化的调控作用

吸烟相关性肺间质病如肺纤维化与吸烟诱发的氧化/抗氧化反应失衡有关。新近报道，血管紧张素转换酶(ACE)- 血管紧张素II（Ang II）-AT1受体轴（简称ACE轴）可促进吸烟诱发的肺纤维化及肺泡上皮细胞凋亡。本前期工作显示，ACE2-Ang（1-7）-Mas轴（简称ACE2轴）则抑制吸烟诱发的上述作用。然而，ACE轴/ACE2轴在此过程中的调节机制尚不明确。我们设想：ACE轴可促进烟草诱发的氧化/抗氧化反应失衡，导致肺纤维化和肺泡上皮细胞凋亡；ACE2轴可抑制上述效应。拟观察Ang II能否促进NOX4-ROS介导的氧化通路或抑制Nrf2-ARE介导的抗氧化通路，促进吸烟诱发的肺纤维化和肺泡上皮细胞凋亡，观察mir-21在其中的作用；观察Ang II诱导的上述作用能否被ACE2及Ang（1-7）抑制。本研究是原有的国家自然科学基金项目向吸烟诱发的肺纤维化的延伸，为肺纤维化防治提供新策略。

Smoking-related interstitial lung disease, such as pulmonary fibrosis, is associated with imbalance between oxidation and antioxidation induced by cigarette smoking. Recent reports have shown that upregulation of ACE-AngⅡ-AT1R axis (ACE axis) promoted pulmonary fibrosis and alveolar epithelial cell apoptosis induced by cigarette smoking. Nevertheless, as our previous studies shown, this effect could be inhibited by ACE2-Ang-(1-7)-Mas axis (ACE2 axis). However, the mechanism about how ACE/ACE2 axis regulates pulmonary fibrosis and cell apoptosis remains unclear. Thus we supposed that ACE/ACE2 axis had positive/negative regulation effects on pulmonary fibrosis and alveolar epithelial cell apoptosis associated with imbalance between oxidation and antioxidation induced by cigarette smoking. To determine the roles of ACE/ACE2 axis and miR-21 in regulating pulmonary fibrosis and alveolar epithelial cell apoptosis induced by cigarette smoking extract (CSE), NOX4-ROS or Nrf2-ARE mediated pathway induced by AngII or CSE will be studied. Besides, whether the above effects induced by AngII or CSE can be inhibited by Ang-(1-7) or lenti-ACE2 remains further studies. Consequently, this project, which is an extension of our original research supported by National Nature and Science Fund, will provide novel strategy for prophylaxis and treatment of smoking-related pulmonary fibrosis.