PECAM-1通过Wnt/β-catenin信号通路介导肺血管内皮通透性改变在SARS-CoV-2相关ARDS中的作用及分子机制

新型冠状病毒(SARS-CoV-2)传染性高，致病性强。重症患者常合并ARDS，病死率高。SARS-CoV-2相关ARDS发病机理尚未阐明。我们研究发现此类患者肺泡死腔增加，提示可能存在肺血管内皮损伤导致肺的微循环障碍，并得到国际同行认可。血小板内皮细胞黏附分子(PECAM-1)是维持血管内皮细胞完整性的重要结构基础，它与β-catenin结合形成复合物组成细胞骨架，在调节血管通透性方面发挥着重要作用。本课题拟通过体外实验新冠病毒刺激人肺微血管内皮细胞和体内构建新冠病毒相关ARDS动物模型结合临床研究，利用RT-PCR、免疫荧光、免疫印迹及腺病毒质粒转载等方法，探讨新冠病毒对肺微血管内皮细胞通透性的影响，阐释PECAM-1通过Wnt/β-catenin通路介导肺血管通透性改变在SARS-CoV-2相关ARDS中的作用及机制。本研究结果为有效防治新冠病毒相关ARDS提供科学依据及药物新靶点。

A novel coronavirus, severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) has spread rapidly around the world and caused severe illness and death. The critically ill patients often develop Acute Respiratory Distress Syndrome (ARDS), leading to a high mortality. Unfortunately, the mechanism underlying SARS-CoV-2 related ARDS remains largely unknown. We have previously demonstrated that increased alveolar dead space is common in COVID-19 associated ARDS patients, suggesting that pulmonary vascular endothelial damage may exit that leads to pulmonary microcirculation disorders. Platelet endothelial cell adhesion molecule (PECAM-1) is an important structural basis for maintaining the integrity of vascular endothelial cells. It combines with β-catenin to form a complex that constitutes a cytoskeletal component and plays an important role in regulating microvascular permeability. Here, we propose to establish an in vitro SARS-CoV-2 related ARDS model through SARS-CoV-2 infected human lung microvascular endothelial cells and an in vivo SARS-CoV-2 infected animal model. In addition, clinical specimen from SARS-CoV-2 related ARDS will be collected and studied as well. RT-PCR, immunofluorescence and Western blotting and adenovirus plasmid transfer technic methods will be performed to explore the effect of SARS-CoV-2 on the permeability change of pulmonary microvascular endothelial cells and the expression of PECAM-1, further explaining the mechanism of PECAM-1 in mediating pulmonary vascular permeability change through the Wnt / β-catenin signaling pathway in SARS CoV-2 related ARDS. The study will provide a potential target for SARS-CoV-2 related ARDS.