AngⅡ通过NOX4/ROS途径介导的氧化应激失衡在H7N9致急性肺损伤中的作用及调控机制研究

H7N9禽流感病情凶险，病死率高，其主要病理特征为氧化应激失衡导致的急性肺损伤。我们前期研究发现：血管紧张素Ⅱ（AngⅡ）表达水平与病程严重程度显著相关。目前研究认为AngⅡ参与调控的NADPH氧化酶4（NOX4）通过调控活性氧自由基（ROS）释放在氧化应激失衡中发挥了重要作用。因此我们推测AngⅡ通过调控NOX4表达促进ROS过量释放导致氧化应激失衡，并进展为急性肺损伤。本项目拟通过构建AngⅡ基因干扰及过表达肺泡上皮细胞株并感染H7N9病毒，比较分析AngⅡ表达水平对NOX4、ROS和氧化应激的调节作用及对细胞损伤程度的影响，并经H7N9感染野生型及AngⅡ受体基因敲除小鼠构建急性肺损伤模型，进一步明确AngⅡ通过其受体AT1R调控NOX4、ROS表达生成的途径，从而探明AngⅡ在H7N9引起急性肺损伤中的确切机制，为开拓新型诊断和治疗靶标、有效救治重症患者提供新思路和新策略。

H7N9 avian influenza is a dangerous disease with high mortality. Its main pathological feature is acute lung injury caused by oxidative stress imbalance. Our previous study found that expression level of angiotensinⅡ (AngⅡ) was significantly associated with severity of disease and was able to predict progression and prognosis of the disease directly. It is currently known that NADPH oxidase4 (NOX4) by regulating the Reactive Oxygen Species (ROS) release, played an important role in oxidative stress imbalance, and AngⅡ participation NOX4 regulation. Therefore, in this study, we assume that AngⅡ promotes excessive ROS release through regulating expression of NOX4, leading to oxidative stress imbalance, and the progression to acute lung injury. We aim to clarify the dose-effect relationship between AngⅡ expression and NOX4, ROS, oxidative stress and cell injury degree. We would also infect wild type and AngⅡ receptor gene knockout mice with H7N9 in order to construct acute lung injury model, clarify AngⅡ regulation NOX4 generated, and NOX4 control way of ROS generation, as well as analyze the exact mechanism of acute lung injury caused by AngⅡ-mediated. It provides new ideas and strategies for developing new diagnostic and therapeutic targets and effective treatment of severe patients.