硫氧还蛋白硝基化在肺纤维化发病中的作用及机制探讨

Pulmonary fibrosis is an epistitial lung disease caused by many lung illnesses, however its etiology has not been revealed. Oxidative stress and apoptosis of alveolar epithelial cells have been reported involved in the pathogenesis of pulmonary fibrosis. As a redox system, thioredoxin(Trx) system plays an important role in various biological events, however its effects in the process of pulmonary fibrosis are not clear. Our previous study showed that the expression of Trx and nitrated Tyrosine increased in lung tissues in pulmonary fibrosis patients, while Trx's activity decreased compared with controls. Thereby, we proposed that Trx nitration takes part in the pathogenesis of pulmonary fibrosis. To support the hypothesis, rats model with pulmonary fibrosis, rat type Ⅱ alveolar epithelial cells will be used in this study. By both in vivo and vitro study using molecular and pathological techniques, whether Trx nitration influences pulmonary fibrosis via p38-MAPK pathway will be studied. Our research will provide new viewpoints about the molecular pathogenesis of pulmonary fibrosis and new targets for its clinical thereapy.

肺纤维化是一组由多种病因引起的间质性肺疾病，其发病率高，目前缺乏有效的治疗手段。肺纤维化的发病多认为与氧化应激诱导的肺泡上皮细胞凋亡有关。硫氧还蛋白系统是体内重要的氧化还原系统。有文献提出，在特发性肺纤维化（IPF）发病过程中，硫氧还蛋白（Trx）代偿性表达增加，但其在IPF发病中翻译后修饰及活性变化缺乏相关研究。我们前期在临床IPF肺组织上研究发现，Trx虽然表达增加，但其活性反而下降，并发现硝基化酪氨酸增加。我们提出假说，Trx硝基化修饰后活性降低，通过诱导肺泡上皮细胞凋亡促进了肺纤维化的进展。为证实这一假说，我们将复制大鼠肺纤维化模型，原代培养大鼠Ⅱ型肺泡上皮细胞，应用分子生物学及病理学技术，从在体和离体两个层面研究Trx硝基化修饰对肺纤维化进程影响及其是否通过p38-MAPK通路介导。本课题将从新的视角阐明肺纤维化发生的分子机制，并为其防治提供新靶点。

肺纤维化是一组由多种病因引起的间质性肺疾病，其发病率高，目前缺乏有效的治疗手段。肺纤维化的发病多认为与氧化应激诱导的肺泡上皮细胞凋亡有关。硫氧还蛋白系统是体内重要的氧化还原系统。有文献提出，在特发性肺纤维化（IPF）发病过程中，硫氧还蛋白（Trx）代偿性表达增加，但其在IPF发病中翻译后修饰及活性变化缺乏相关研究。我们研究发现，Trx虽然表达增加，但其活性反而下降，并发现硝基化酪氨酸增加。我们复制大鼠肺纤维化模型，原代培养大鼠Ⅱ型肺泡上皮细胞，应用分子生物学及病理学技术，从在体和离体两个层面研究Trx硝基化修饰对肺纤维化进程影响及其是否通过p38-MAPK通路介导。本课题将从新的视角阐明肺纤维化发生的分子制，并为其防治提供新靶点。同时，我们在课题进行中，研究了细胞自噬在肝纤维化发病中作用，并探讨了胸腺素β4对肝纤维化的保护作用。