Rab26调控肺巨噬细胞线粒体自噬-LAP轴遏制炎症失控致ARDS的机制

急性呼吸窘迫综合征（ARDS）是脓毒症时炎症失控导致弥散性肺泡损伤，常发展为呼吸衰竭，而肺巨噬细胞吞噬功能异常可诱发不可控炎症；我组既往发现内毒素破坏巨噬细胞的线粒体自噬（mitophagy）及LC3相关吞噬作用（LAP），而Rab26可调节mitophagy和LAP。提出假设：Rab26囊泡转运调控肺巨噬细胞的mitophagy-LAP轴，维持肺组织炎症可控性；脓毒症时破坏线粒体自噬及LAP，诱发炎症消退障碍，导致炎症失控。该项目应用条件敲除鼠Rab26M-/-、EPORM-/-以及双敲鼠Rab26M-/-EPORM-/-、FACS分选敲除鼠等BALF中巨噬细胞、Co-IP分析Rab26与EPOR等相互作用等方法，探索脓毒症时Rab26对巨噬细胞线粒体自噬及LAP的作用，Rab26调控炎症消退的机制，为防治ARDS探索新机制及新靶点。

Acute respiratory distress syndrome (ARDS) is a disorder of diffuse alveolar injury caused by uncontrolled inflammation including sepsis, which leads to respiratory failure. Of note, autophagy disorder of pulmonary macrophages can induce uncontrollable inflammation. We have previously found that mitochondrial autophagy and LC3-associated phagocytosis (LAP) of macrophages could be impaired by endotoxin, while Rab26 can regulate mitophagy and LAP. The hypothesis is that Rab26‐mediated trafficking maintains the normal mitophagy and LAP of pulmonary macrophages, and controls the inflammation levels in lung tissue, while sepsis makes LAP disruptive and delayed resolution of inflammation, leading to inflammation out of control. This project uses conditioned knockout mice Rab26M-/-, EPORM-/-and Rab26M-/-EPORM-/-, isolated macrophages from knock out mice BALF by FACS sorting, and Co-IP analysis of Rab26 interaction with EPOR and other methods, to explore the role of Rab26 on mitophagy and LAP of macrophages during sepsis-induced ARDS. To investigate the new mechanisms and targets for the prevention and treatment of ARDS.