肝肺综合征防治困难，核心原因是迄今为止“衔接病肝和肺部改变的关键因素不明”、“HPS重症化分子机制不明”等瓶颈问题还未解决。我们在前期预实验基础上，结合最新文献报道，提出了“慢性病肝胆管上皮细胞分泌BMP9增加→释放入血→作用于肺PMVECs 胞膜ALK1受体→激活下游Endoglin通路→PMVECs细胞骨架重塑以及纤毛数量和长度增加→获得增殖和移行能力→PPA形成→HPS重症化”的假说。由此本课题拟利用大鼠HPS在体、离体模型以及HPS患者组织，采用免疫组化、转基因技术、光遗传学技术、FRET等方法，明确病肝来源BMP9在HPS重症化中的作用；阐明其通过活化ALK1/Eng通路调控PMVECs骨架重塑以及纤毛数量长度增加，进而促进PPA形成的具体机制，由此验证BMP9-ALK1/Endoglin途径作为HPS重症化防治全新靶点的可行性，为获得更佳保护的HPS防治新策略奠定一定理论基础。

The main reason for the difficulty in preventing and curing Hepatopulmonary syndrome was that the key factors that link the diseased liver and lung change were unknown and the molecular mechanism of HPS aggravation was not elucidated. On the basis of our preliminary experiments combined with the latest literature, we put forward the hypothesis——Increasing and releasing of BMP9 secreted by biliary duct epithelial cells in chronic liver disease into blood→ effection on PMVECs cell membrane ALK1 receptor to activating downstream Endoglin pathway→remodeled cytoskeleton of PMVECs and increased number and length of cilia to obtain the ability of proliferation and migration→formation of PPA→HPS aggravation. This subject use the rat models of HPS in vivo/vitro and tissues in patients with HPS by immunohistochemistry, transgenic technology, light genetics and FRET methods. We intends to clarify the role of liver- secreted BMP9 in the HPS aggravation and to clarify the specific mechanism of activation of ALK1/Endoglin pathway by BMP9 to regulates PMVECs skeleton remodeling and the increase of number and length of cilia, and then promote the the formation of PPA, thus verifying the feasibility of BMP9-ALK1/Endoglin pathway as a new target for the prevention of HPS aggravation and laying a theoretical foundation of new strategies for better prevention and treatment of HPS.