Humanin通过介导线粒体代谢保护脓毒症急性呼吸窘迫综合征肺血管内皮细胞的机制研究

Humanin（HN）作为线粒体DNA编码的一种保护性多肽，对脓毒症ARDS的肺血管内皮细胞具有显著的保护作用。在前期研究中，我们发现HN能显著降低LPS诱导的ARDS小鼠的死亡率，减轻肺组织炎症及渗出，并且降低肺血管内皮细胞的氧化应激水平，增强内皮细胞活性。进一步研究发现，HN可恢复由LPS导致的ATP产量下降。但是，HN保护内皮细胞结构与功能完整性的具体机制尚未明确。本研究拟通过体内外实验明确HN是否通过影响线粒体代谢对肺血管内皮细胞起保护作用；进一步利用内皮细胞特异性IL-6R敲除小鼠以及PI3K敲除小鼠，明确HN在肺血管内皮细胞上的结合位点，探讨其影响线粒体代谢功能的具体机制；同时与临床相结合，研究HN与脓毒症ARDS病人预后的相关性，为治疗脓毒症导致的ARDS提供新的治疗策略。

Humanin (HN), as a protective polypeptide encoded by mitochondrial DNA, has an important protective effect on pulmonary vascular endothelial cells in septic ARDS. In our previous studies, we found that HN could significantly reduce the mortality of LPS-induced ARDS mice, lighten the lung inflammation and exudation, alleviate the oxidative stress level of pulmonary vascular endothelial cells, and enhance endothelial cell activity. Furthermore, we found that HN can restore the ATP production which was cut down by LPS to a certain extent. However, the specific mechanism by which HN protects the structural and functional integrity of endothelial cells is not yet clear. This study wishes to clarify through in vivo and in vitro experiments that HN protects pulmonary vascular endothelial cells by protecting mitochondrial metabolism; and intends to use endothelial cell-specific IL-6R knockout mice and PI3K knockout mice to explore the binding sites and the definite mechanisms of HN on pulmonary vascular endothelial cells. At the same time, through the combination of clinical and basic scientific research, the prognosis of patients with septic ARDS will be studied to provide new therapy strategies for the treatment of ARDS caused by sepsis.