脓毒症患者血浆胞外囊泡诱发急性肺损伤的机制研究

尽管近年来肺保护通气和液体管理技术有较大进展，急性呼吸窘迫综合征（急性肺损伤）的死亡率依然高达30-40%。我们前期研究发现经气管给予脓毒症休克患者血浆胞外囊泡后，小鼠肺泡灌洗液中总细胞数和促炎细胞因子水平显著升高。与健康对照组相比，miRNA芯片结果显示脓毒症患者血浆胞外囊泡有11种miRNA表达增加2倍以上，而且其中let-7d-3p可诱导小鼠M1型巨噬细胞极化。另外，let-7d-3p含有结合Toll样受体7和8（TLR7/TLR8）的基序。本课题假设①脓毒症患者血浆胞外囊泡转移至肺泡巨噬细胞并诱发急性肺损伤；②脓毒症小鼠血浆胞外囊泡通过传递let-7d-3p至肺泡巨噬细胞而发挥作用；③最后，let-7d-3p激活TLR7/TLR8-MyD88-NF-κB信号通路。以上假设均为全新思维。本课题有助于阐明脓毒症性急性肺损伤的分子机制，let-7d-3p可能成为其治疗的潜在靶点。

Despite improvements in lung-protective ventilation and fluid management, the mortality of ARDS still remains as high as 30-40%. For the past 10 years, extracellular vesicles (EVs) have been recognized as a novel mechanism of intercellular communication by transferring cellular components. It has been documented that circulating EVs from septic shock patients induced system inflammatory response in mice. In the preliminary studies, we found that intratracheal administration of plasma EVs from septic shock patients significantly elevated the number of total cells and pro-inflammatory cytokine levels in the bronchoalveolar lavage fluid. Microarray analysis showed 11 miRNAs with greater than 2 fold increase in the plasma EVs from sepsis patients compared with healthy controls.Among the elevated miRNAs, let-7d-3p induced M1 macrophage polarization. In addition, let-7d-3p contains motifs that bind to Toll-like receptors 7 and 8 (TLR7/TLR8). In this grant application, we hypothesize that plasma EVs from sepsis patients are transferred to alveolar macrophages and induce acute lung injury (hypothesis 1). Secondly, plasma EVs from septicmiceexert their effects via transfer of let-7d-3p to alveolar macrophages (hypothesis 2). Furthermore, let-7d-3p activates the TLR7/TLR8-MyD88-NF-κB signaling pathway (hypothesis 3).To the best of our knowledge, the proposed studies have not been reported in the literature. The studies may provide new insights into the mechanisms of sepsis-induced acute lung injury and let-7d-3p maybecome a potential therapeutic target for treating sepsis-induced acute lung injury.