经颈静脉肝内门体静脉分流术(TIPS)是目前控制门静脉高压症最有效的方法之一，但较高的肝性脑病发生率严重制约术后疗效。我们前期研究发现TIPS后肝性脑病的发生率与外周血中HMGB1含量及肝组织炎症程度呈正相关，而HMGB1又在促进机体炎性反应，增加炎性因子水平和血脑屏障内皮细胞通透性中起关键作用。据此提出假说：HMGB1是促进肝性脑病症状的重要炎性介质，其机制为通过RAGE/p-ERM通路影响脑内皮细胞紧密连接ZO-1，从而增加血脑屏障通透性，使脑内毒性物质聚集导致肝性脑病的发生。本研究拟通过体外模型观察HMGB1对血脑屏障的影响及与肝性脑病的相关性；通过基因敲除和过表达HMGB1、RAGE和Moesin基因，明确HMGB1激活RAGE通路下游的p-ERM降低内皮细胞表达ZO-1、引起血脑屏障内皮通透性增高、诱发肝性脑病的分子作用机制，本研究旨在为TIPS术后为肝性脑病的治疗提供新靶点。

Transjugular intrahepatic portosystemic shunt (TIPS) placement is a well-established procedure for the treatment of complications in patients with cirrhosis with portal hypertension. However, the results are discordant with regard to high risk of hepatic encephalopathy (HE). Our previous study found that the incidence of Post-TIPS HE is positively correlated with the levels of HMGB1 in peripheral blood and the severity of inflammation of liver tissue, and HMGB1 play a key role in promoting the inflammatory response with cytokines as well as the permeability of endothelial tight junctions. Therefore, we hypothesize that HMGB1 effect on the expression of ZO-1 of tight junction in brain microvascular endothelial cells(MECs) through RAGE/p-ERM pathway, which is thought to be the important factor to the HE inflammations, thereby leading to occurrence of this disease with increased blood-brain barrier permeability and toxic substances in the brain. This study shall establish the models in vitro to clarify the correlation among HMGB1, hepatic encephalopathy and blood-brain barrier permeability. By knockout and overexpression of HMGB1, RAGE and Moesin genes, it was clarified the molecular mechanism of hyperpermeability induced by HMGB1 in brain MECs through RAGE/p-ERM activation reducing the expression of ZO-1. As a result, hepatic encephalopathy is occurred with increased blood-brain barrier permeability and toxic substances in the brain. This study can provide a new target for the treatment of hepatic encephalopathy.