间充质干细胞来源Let-7d在脓毒症致急性肺损伤中的作用及机制研究

The lungs are the most vulnerable organs in sepsis. Macrophages, as the tissue-residence sentinel cells, play a key role in the innate immune response, and M1/M2 macrophage polarization is the very important regulatory response which mediates the initiation and development of ALI/ARDS. Recent studies have shown that MSC can educate macrophages to modulate immune response and alleviate acute lung injury through releasing microRNAs. In our preliminary studies, we found that sepsis induced ALI was alleviated by MSC-educated macrophages infusion in vivo. In vitro, level of Let-7d was significantly up-regulated in educated macrophages and M2 macrophages were increased. Therefore, we hypothesis that MSC-derived Let-7d will be involved in the pathogenesis of acute lung injury via modulating the M1/M2 macrophage polarization and inflammatory response. The present project will, from the systemic, cellular and molecular levels, analyze the correlation between macrophages educated by MSC derived Let-7d and acute lung injury induced by sepsis, to clarify the roles of Let-7d modulating macrophages polarization and inflammation modulation, and subsequent to explore the signal pathway how Let-7d regulate macrophage polarization. This study will provide new ideas and targets in the prevention and management of ALI induced by sepsis.

肺脏是脓毒症中受累的首位靶器官，巨噬细胞作为组织居留型前哨细胞是固有免疫的关键抗感染细胞，M1/M2型巨噬细胞极化是参与调节ALI/ARDS发生发展的关键环节。最近研究发现间充质干细胞（MSC）通过其释放的microRNAs作用于巨噬细胞调控炎症免疫反应，从而减轻急性肺损伤。我们前期实验发现：回输MSC驯化的巨噬细胞减轻了小鼠脓毒症致急性肺损伤，体外研究发现驯化的巨噬细胞内Let-7d高表达、同时巨噬细胞往M2型极化。因此，我们推测，间充质干细胞来源的Let-7d通过调控巨噬细胞往M2型极化、调节炎症反应，参与脓毒症致ALI的发生发展。本项目拟从整体、细胞和分子水平，明确间充质干细胞分泌的Let-7d调控巨噬细胞极化与脓毒症致ALI发生、发展的相关性，深入探讨Let-7d调控巨噬细胞极化的分子机制，为脓毒症致ALI防治提供新思路、新靶标。

肺脏是脓毒症中受累的首位靶器官，巨噬细胞作为组织居留型前哨细胞是固有免疫的关键抗感染细胞，M1/M2型巨噬细胞极化是参与调节ALI/ARDS发生发展的关键环节。最近的研究表明，骨髓间充质干细胞来源的细胞外小泡能够模拟骨髓间充质干细胞减轻急性肺损伤。研究结果表明，年老和年轻的MSC-EVs具有相似的物理和表型特性。移植年轻MSCs可减少炎症细胞的涌入，减少肺泡间隔增厚，而年老的MSCs则失去上述作用。与年轻的MSC-EVs相比，年老的MSC-EVs未能改变巨噬细胞表型并减少巨噬细胞募集，且年老的MSC-EVs被巨噬细胞内化的能力明显低于年轻的MSC-EVs。此外，与衰老MSC-EV相比，年轻MSC-EVs中miR-223-5p的表达较高，miR-127-3p和miR-125b-5p的表达水平较低。