脂肪组织源循环外泌体通过miR221/ETS1调控肺微血管内皮细胞屏障稳态在ARDS肥胖悖论中的作用及机制研究

Imbalanced homeostasis of pulmonary microvascular endothelial barrier is the pathophysiological foundation of hyper-permeability induced lung edema. “Obesity paradox in ARDS” refers to the phenomenon that obesity is associated with lower mortality in patients with ARDS. Our previous studies have found that various adipokines secreted by adipose tissue exert beneficial actions on endothelial barrier homeostasis in setting of ARDS. Recent researches show that adipose tissue constitutes a major source of circulating exosomal miRNAs, and these miRNAs can regulate gene expression in distant tissues thereby serving as genetic forms of adipokines. Adipose tissue is now appreciated as an important endocrine tissue that contributes to the progression of ARDS, while there have been few researches on adipose-lung crosstalk. A panel of molecular biotechniques were utilized to investigate the effects and mechanism of adipose-derived circulating exosomal miR-221 and its target gene ETS1 in the regulation of endothelial adherens junctions protein VE-cadherin, thus promoting the pulmonary endothelial barrier homeostasis under ARDS, which is valuable for the precision medicine of ARDS.

肺微血管内皮细胞屏障稳态失衡是ARDS渗透性增高性肺水肿的病理生理基础。肥胖人群较体重正常体重人群ARDS病死率显著降低，谓之“肥胖悖论”。我们前期研究发现，脂肪组织可通过分泌诸多脂肪细胞因子介导ARDS肺微血管内皮细胞屏障稳态的保护性调控。新近研究发现，脂肪组织是外周循环外泌体microRNAs的主要来源，并作为基因型脂肪细胞因子参与远隔器官功能调控。脂肪组织作为机体重要的内分泌器官，对ARDS发挥重要调控效应，但目前脂肪组织与肺脏之间交互作用相关研究甚少。本项目拟运用多种分子生物学技术，深入探讨脂肪组织源循环外泌体microRNA-221及其靶基因ETS1介导的内皮细胞间黏附连接蛋白VE-cadherin的调控在ARDS肺微血管内皮屏障稳态维持中的作用及机制，以期为ARDS精准医疗提供新思路。

肥胖人群较体重正常体重人群急性呼吸窘迫综合征（ARDS）病死率显著降低，谓之“ARDS肥胖悖论”。内屏间质转化（EndMT）是调控肺损伤内皮屏障损伤修复和基质纤维沉积的关键交叉节点，亦是肺功能及结构稳态有效维系的重要机制。我们发现，脂肪组织作为循环外泌体microRNAs的主要来源，并作为基因型脂肪细胞因子参与ARDS内皮屏障功能调控。与正常体重小鼠相比，高脂饮食诱导肥胖小鼠循环外泌体及脂肪组织的miR-122-5p水平明显升高。体内外多项分子机制研究证实，miR-122-5p可通过抑制TGFβ1/TGFβR1/Smad2 pathway 信号通路，减轻EndMT过程，对 ARDS肺微血管内皮细胞屏障损伤及间质纤维化增生发挥保护性调控效应。本研究为ARDS肥胖悖论及基于外泌体的无细胞移植治疗手段提供理论依据。

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