间充质干细胞驯化的巨噬细胞通过IL-10减轻肺损伤的机制研究

The mortality for acute respiratory distress syndrome (ARDS) remains high, even with the current advances in lung-protective ventilation and fluid management. Our group was the first to demonstrate that mesenchymal stem cells (MSC) attenuate the LPS-induced lung injury and report the application of MSC in ARDS trial. Recent studies have shown that macrophages previous cocultured with MSCs (MSCs-educated macrophages) could alleviate colitis in an animal model. In our preliminary studies, we found that educated macrophages alleviated LPS-induced lung injury. In vitro, MSC altered the cytokine profile of macrophages induced by LPS through an IL-10-dependent mechanism. In this grant application, we hypothesize that MSCs-educated macrophages reduce LPS-induced lung injury via IL-10 (hypothesis 1). Secondly, educated macrophages decrease neutrophil recruitment via IL-10 (hypothesis 2). Furthermore, we hypothesize that educated macrophages exert the anti-inflammatory effects via IL-10/STAT3 pathway. The proposed studies may provide new insights into the mechanisms of educated macrophages on acute lung injury and may also reveal evidences that educated macrophages might be a potential strategy for treating ARDS.

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（ARDS）的死亡率依然居高不下。我们团队首先发现间充质干细胞能够改善小鼠 LPS 诱导的急性肺损伤，并首先报道了间充质干细胞在 ARDS 的临床试验初步结果。最近研究表明，间充质干细胞驯化的巨噬细胞能减少在结肠炎中小鼠的死亡和体重减轻。我们前期研究证明了驯化巨噬细胞对促炎因子 IL-6和TNF-α的减低作用依赖于 IL-10 的表达。在体内，直接输注驯化巨噬细胞改善了 LPS诱导的肺损伤并提高 IL-10。本课题假设①间充质干细胞驯化的巨噬细胞通过 IL-10减轻 LPS诱导的肺损伤；②驯化巨噬细胞通过 IL-10减少 LPS诱导的中性粒细胞的募集；③最后，驯化巨噬细胞通过 IL-10/STAT3信号通路自我调节而产生抗炎作用。本课题有助于阐明驯化巨噬细胞减轻肺损伤的作用机制，为直接用驯化巨噬细胞治疗ARDS提供重要依据。

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（ARDS）/急性肺损伤（acute lung injury, ALI）的死亡率依然居高不下。ARDS的发病率随着年龄的增长而上升，而老年患者的死亡率更高。在国家自然科学基金资助下，本课题（间充质干细胞驯化的巨噬细胞通过IL-10减轻肺损伤的机制研究，81570071）研究发现间充质干细胞（MSCs）驯化的巨噬细胞通过IL-10通路减轻LPS诱导的全身和肺部炎症，并促进M2型巨噬细胞表达。进一步研究发现老年和年轻MSCs来源的胞外囊泡（MSC-EVs）对减轻急性肺损伤和调控巨噬细胞极化发挥不同作用。