线粒体DNA介导的高原肺水肿炎症机制研究

项目名称： 线粒体DNA介导的高原肺水肿炎症机制研究

项目编号： No.81471814

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 高文祥

作者单位： 中国人民解放军第三军医大学

项目金额： 73万元

中文摘要： 线粒体和炎症反应均在高原肺水肿(HAPE)发生中具有重要作用。我们最近研究发现，缺氧和炎症反应降低线粒体DNA(mtDNA)稳定性是HAPE发生的一个重要机制，但线粒体损伤是否反馈激活炎症反应并参与HAPE发生尚乏研究。研究表明，若线粒体损伤超过机体自身的清除能力(线粒体自噬)，mtDNA释放增多，可通过TLR9(Toll like receptor 9)激活炎症反应。我们前期研究发现，HAPE患者血浆mtDNA水平显著高于高原健康者；静脉注射mtDNA可致缺氧大鼠肺含水量显著升高，提示mtDNA介导的炎症反应可能参与HAPE发生。本项目拟从临床、动物和离体细胞水平，研究揭示mtDNA介导的炎症反应在HAPE发生中的作用，探讨其关键信号通路和作用分子，阐明HAPE线粒体损伤-清除失衡及其激活炎症反应的机制。本研究有望取得HAPE发生机制研究的新突破，为临床HAPE防治提供新线索和分子靶点。

中文关键词： 高原肺水肿；线粒体DNA；炎症反应；缺氧；分子机制

英文摘要： Mitochondria and inflammation both contribute a lot to the development of high altitude pulmonary edema (HAPE). Our recent study indicates that hypoxia and inflammation can lead to instability of mitochondrial DNA (mtDNA), which is a critical factor of HAPE. However, there is a lack of study on crosstalk between mitochondrial injury and inflammation in HAPE. It has been proved that once mitochondria are injured more than that the body can clear with the machineries of mitophagy, mtDNA will be released and induce inflammatory reaction via Toll like receptor 9 (TLR9). We just found that plasma mtDNA was significantly higher in HAPE patients than the healthy control at high altitude, and mtDNA administration can increase wet/dry ratio of lung tissue in hypoxic rats, suggesting a critical role of the inflammation induced by mtDNA in HAPE development. In this project, we plan to study HAPE patients, HAPE rats and in vitro cultured alveolar microphagy, to clarify mechanisms of mtDNA induced inflammation in the pathophysiology of HAPE, to elucidate the trigger of mtDNA release after hypoxic exposure, and to pin point key moleculars as new therapeutic targets of HAPE.

英文关键词： high altitude pulmonary edema;mitochondrial DNA;inflammation;hypoxia;molecular mechanism