PINK1/Parkin介导的线粒体自噬在氢气治疗脓毒症肺损伤中的作用机制研究

Lung injury is the leading cause of death in patients with sepsis. Abnormal mitophagy is one of the key mechanisms of organ damage induced by sepsis. Our studies have found that hydrogen obviously alleviated lung injury in septic mice, autophagy regulated lung injury in sepsis, and parkin participated in the process of hydrogen treatment on lung injury. But the specific mechanismes of hydrogen improving lung injury is not clear. In this research, we will investigate the mechanism of PINK1/Parkin-mediated mitophagy on hydrogen treatment of sepsis-induced lung injury. On the basis of the sepsis-induced lung injury in vivo and LPS-stimulated macrophage in vitro, using the molecular biological technologies of western blot, RT-PCR, immunofluorescence and RNAi, from animals to cells to molecules, we will confirm 1) the effect of mitophagy on lung injury in sepsis; 2) hydrogen improving lung injury via mitophagy; 3) the mechanism of PINK1/Parkin on hydrogen regulating mitophagy. The project is expected to provide a theoretical basis for the clinical treatment in patients with sepsis and for finding drug targets of sepsis treatment.

肺损伤是脓毒症患者死亡的主要原因，线粒体自噬异常是脓毒症器官损伤的关键机制之一。本课题组前期发现氢气明显减轻脓毒症小鼠肺损伤，且自噬可调控脓毒症肺损伤，与Parkin蛋白表达有关，但具体机制仍不清。本项目拟探讨PINK1/Parkin介导的线粒体自噬在氢气治疗脓毒症肺损伤中的分子机制，采用Western blot、RT-PCR、免疫荧光和RNA干扰等分子生物学技术，在脓毒症小鼠肺损伤和巨噬细胞培养模型的基础上，从整体、亚细胞和分子水平等不同层次证明：1）线粒体自噬在脓毒症肺损伤中的作用；2）氢气调控线粒体自噬改善脓毒症肺损伤；3）PINK1/Parkin在氢气调控线粒体自噬中的具体机制。上述研究结果将为氢气治疗脓毒症的临床应用奠定理论基础，为研发治疗脓毒症的药物靶点提供依据。

肺损伤是脓毒症患者死亡的主要原因，线粒体自噬异常是脓毒症器官损伤的关键机制之一。本课题组前期发现氢气明显减轻脓毒症小鼠肺损伤，且自噬可调控脓毒症肺损伤，与Parkin蛋白表达有关，但具体机制仍不清。本研究主要探讨PINK1/Parkin介导的线粒体自噬在氢气治疗脓毒症肺损伤中的分子机制，采用Western blot、RT-PCR、免疫荧光和RNA干扰等分子生物学技术，在脓毒症小鼠肺损伤和巨噬细胞培养模型的基础上，从整体、亚细胞和分子水平等不同层次证明：线粒体自噬在脓毒症肺损伤中发挥保护作用；氢气通过调控线粒体自噬改善脓毒症肺损伤，且这一作用通过激活PINK1/Parkin介导的线粒体自噬实现的。除此之外，我们还发现脓毒症可诱发NLRP3炎症小体的激活，氢气通过自噬减轻脓毒症小鼠炎症小体的激活，进而发挥保护作用。氢气还通过自噬与内质网(ERS)的“串话”脓毒症器官功能障碍的保护作用。上述研究结果将为氢气治疗脓毒症的临床应用奠定理论基础，为研发治疗脓毒症的药物靶点提供依据。