Maresin1 调控巨噬细胞表型转化在肺损伤中的作用及其机制

Acute lung injury (ALI) is the major cause of death in acute and severe diseases, and macrophage polarization plays an important role on inflammatory resolution of ALI. Our previous studies have shown that Maresin 1 mitigates lipopolysaccharide-induced ALI in mice, however, the protective mechanism is unclear. Therefore, we established the hypothesis that Maresin 1 promotes resolution of ALI through regulating the macrophage polarization. This study is aimed to use ALI in mice induced by intratracheal instillation of lipopolysaccharide, and inflammatory cytokines-stimulated cultured RAW264.7 as the research objects. We investigate the impacts of Maresin 1 on inflammation of ALI, macrophage phagocytosis and macrophage polarization, and evaluate the cellular and molecular events and vital signaling pathways or regulating signal molecules that contribute to macrophage polarization. This therapy will provide a basis for subsequent clinical translation.

急性肺损伤（ALI）是临床上常见的急危重症的死亡原因，巨噬细胞表型转化在ALI炎症消退过程中发挥着重要的作用。在前期研究发现Maresin 1能减轻小鼠ALI的发生，但其保护机制不清楚。因此，我们进一步提出了“Maresin 1通过增强巨噬细胞表型转化，促进ALI炎症消退”的假说。本研究拟以脂多糖气管内滴注建立小鼠急性肺损伤模型和细胞因子刺激的培养小鼠巨噬细胞RAW264.7为研究对象，动态观察Maresin 1对肺损伤炎症、巨噬细胞吞噬和表型转化功能的影响，同时明确与巨噬细胞表型转化相关的分子事件、发现关键信号通路或调控分子，最终为后续的临床转化提供理论依据。

急性肺损伤(Acute lung injury, ALI)及其严重形式急性呼吸窘迫综合征(Acute respiratory distress syndrome, ARDS)是一种以毛细血管内皮肺泡-上皮屏障破坏为特征的临床疾病，可导致肺水肿，损害呼吸系统的正常功能。尽管临床上采取了多种治疗手段，但ALI/ARDS的发病率和死亡率仍然很高。Maresin 1 (MaR1)是一种新型的由二十二碳六烯酸衍生的促炎症消退介质，可促进炎症的消退。我们前期的研究报道显示MaR1可减轻急性肺损伤，但其相关机制尚不清楚。通过肺上皮细胞的离体实验和脂多糖诱导的急性肺损伤在体实验，我们发现MaR1通过上调紧密连接蛋白-1和ZO-1的表达，维持肺上皮细胞的通透性。同时，通过结肠结扎-穿孔（CLP）手术建造小鼠脓毒症模型，MaR1通过促进巨噬细胞向M2分化，增强巨噬细胞吞噬功能，从而减轻脓毒血症的全身炎症反应。此外,我们进一步研究证实MaR1通过促进巨噬细胞表型转化，加速脂多糖诱导的急性肺损伤炎症消退，其机制可能与PPAR-γ的激活有关。