呼吸机诱导肺损伤(VILI)后组织修复与患者预后密切相关。巨噬细胞极化为促炎/抑炎的M1/M2亚群对修复至关重要。Wnt通路能调控巨噬细胞炎症，在VILI后激活，但对其介导巨噬细胞极化、参与VILI后组织修复的作用和机制还知之甚少。我们前期在小鼠VILI模型发现肺M2型巨噬细胞分化延迟并持续浸润，影响修复；肺巨噬细胞Wnt5a/Fz8通路持续激活。据此提出假说：VILI异常激活巨噬细胞非经典Wnt5a/Fz8通路，抑制M2型分化，导致极化失衡，造成肺组织修复障碍及纤维化，肺保护性通气通过上述机制改善修复。我们拟以巨噬细胞极化为切入点，在体复制野生型和Fz8敲除小鼠VILI模型，并与肺保护性通气模型相对比，离体采用巨噬细胞与肺泡上皮或成纤维细胞共培养，利用流式细胞术、转录组测序等方法研究巨噬细胞亚群和功能变化，以期揭示该通路在VILI后组织修复中的作用及机制，为改善VILI预后提供分子靶点。

Tissue repair following ventilator induced lung injury (VILI) is closely related to the patient prognosis. It is essential that macrophage polarizes to pro- or anti-inflammation subset, named M1 or M2, in the process of repair. Wnt signaling pathway has been proved to regulate macrophage inflammatory response, as well, to be activated by VILI. However, it is still poorly known what the role of Wnt signaling pathway plays in macrophage polarization and tissue repair following VILI. Previously, we found the VILI mouse model exhibited procrastination of M2 subgroup macrophage differentiation and infiltration, which interferenced lung tissue repair and promoted fibrosis. Our preliminary result also showed Wnt5a and its receptor Fz8 sustained increase in pulmonary macrophages after VILI, which upregulating the activation of noncanonical downstream. Consequently, we hypothesize : VILI induced abnormal activation of macrophagic noncanonical Wnt5a/Fz8 signaling pathway inhibits M2 subset switching and leads to imbalance of macrophage polarization，resulting in lung tissue repair suppression and pulmonary fibrosis; lung protective ventilation may improve repair via suppressing above signaling pathway. In this study, we plan to prove our hypothesis in vivo through using the wild type, Fz8 knockout and bone marrow transplantation mice with VILI and protective ventilation model. Moreover, macrophages with alveolar epithelial cells or fibroblasts will be co-cultured in vitro. Flow cytometry analysis and transcriptome sequencing will be applied to investigate the mechanism underlying our preliminary findings. Within this study, we anticipate to explore a novel therapeutic target to improve recovery from VILI.