A2aR/HIF-1/TIM-3信号通路对缺氧应激条件下肝脏窦内皮细胞活化及肝窦微循环紊乱的调控机制研究

缺血再灌注损伤严重影响肝脏移植预后，肝脏窦内皮细胞（LSEC）是调控炎症细胞趋化及肝窦微循环障碍的关键节点。我们前期观察到活性氧能够诱导LSEC表面的TIM-3分子；阻断TIM-3会导致LSEC过度激活；TIM-3的表达受腺苷受体A2aR的调节。但TIM-3在LSEC缺氧应激中发挥的作用及其机制仍未明确。在大脑免疫细胞中有研究发现HIF-1能够结合TIM-3的启动子区域调控TIM-3表达，而另一项研究证实视网膜内皮缺氧后腺苷受体A2aR活化能够促进HIF-1α表达。因此我们提出假设：缺氧导致的A2aR活化能够通过转录因子HIF-1α影响LSEC表面TIM-3的表达，并进一步调控LSEC的活化和肝窦微循环状态。本项目拟在前期研究基础上，以TIM-3的功能及其活化途径为切入点，探讨A2aR/HIF-1/TIM-3通路在LSEC中可能的作用机制，为临床减轻肝脏IRI损伤提供新的理论依据和策略。

Liver sinusoidal endothelial cells (LSEC) are the first barrier to hypoxia injury and play an important role in maintaining the sinusoidal microcirculation homeostasis. Our previous study implied that TIM-3 might be involved in the activation of LSEC during hypoxia injury. A recent study has demonstrated that HIF-1 in mouse brain immune cells can bind to the promoter region of TIM-3 gene and regulates local inflammatory responses by activating TIM-3. While another study confirmed that activation of adenosine receptor A2aR can promote HIF-1α expression after retinal endothelial hypoxia. Therefore, we use the conditional gene knockout mice in liver IRI model to explore the role of A2aR/HIF-1/TIM-3 signaling pathway. The mechanism underline could provide a new strategy for clinical treatment of hepatic ischemia reperfusion injury.