脂联素通过调控Nrf2-ARE-HMGB1通路保护心肺复苏后的血脑屏障的机制研究

Cardiac arrest (CA) results in unfavorable blood-brain barrier (BBB) breakdown in most returning of spontaneous circulation patients for the ischemia-reperfusion injury (IRI) induced by CA-cardiopulmonary resuscitation (CPR). BBB injury after CPR involves various factors and pathways, in which reactive oxidative stress (ROS) and inflammatory reaction has been proved to be the major causes of it. However, capable therapeutics to CA-CPR induced BBB injury is still lacking. Our previous studies revealed that adiponectin (APN) is capable in inhibiting of inflammatory reaction induced by ROS as well as reducing the BBB permeability in a CPR mouse model. However, the specific molecular mechanism of it remains unknown. Therefore, in the present study, we sought to conduct the experiment on knockout mice, using Gd-DTPA magnetic resonance imaging and plasmid transfection technology to explore the effects of APN on maintaining BBB integrity, the regulation of Nrf2-ARE-HMGB1 signal pathway, anti-apoptosis and even the anti-degradation of basement membrane at molecular, cellular and animal level. Taken together, the aim of this study was to: 1) uncover the interaction between Nrf2-ARE and HMGB1; 2) and then to confirm whether APN effects on CA-CPR induced BBB damage via modulating the Nrf2-ARE-HMGB1 signal pathway, with the ultimate expects to improve the survival rate and reduce the disability rate of patients suffered from CA.

心脏骤停（CA）患者经心肺复苏（CPR）恢复自主循环后，因缺血再灌注（IR）引起的血脑屏障(BBB)损伤，目前尚无有效的防治手段。学界认为，CPR后BBB的损伤与氧化应激、炎性反应有关。本课题组的研究发现，脂联素(APN)可减轻氧化应激引起的炎性反应以及CPR后小鼠BBB的损伤，但具体分子机制尚不清楚。本研究利用基因敲除、Gd-DTPA磁共振、质粒转染等技术，从分子、细胞和动物水平深入研究APN逆转CPR所致BBB损伤、调控Nrf2-ARE-HMGB1通路、细胞凋亡、基底膜损伤等情况，揭示Nrf2-ARE与HMGB1间的作用关系，探讨APN通过调控Nrf2-ARE-HMGB1通路减轻CA引起的BBB损伤的分子机制，为早期阻断CA-CPR引起的BBB损伤寻找新的切入点，对提高CPR患者的生存率，降低致残率具重要意义。

心脏骤停（CA）患者经心肺复苏（CPR）恢复自主循环后，因缺血再灌注（IR）引起血脑屏障(BBB)损伤，目前尚无有效的防治手段。学界认为，CPR后BBB的损伤与氧化应激、炎性反应有关。课题组既往研究发现，脂联素(APN)可减轻氧化应激引起的炎性反应以及CPR后小鼠BBB的损伤。本项目按计划探究APN减轻CPR所致BBB损伤是否与调控Nrf2-ARE-HMGB1通路有关。.项目执行顺利，利用基因敲除、透射电镜、激光共聚焦、免疫荧光、Western blot等技术，从分子、细胞和动物水平，观察APN逆转CPR所致BBB损伤的表型和变化，调控Nrf2-ARE-HMGB1通路、细胞凋亡等情况，证实APN增强缺血再灌注诱导的Nrf2信号通路激活，促进小胶质细胞表型转换，抑制炎症反应抗脑微血管内皮细胞间紧密连接破坏，最终减轻全脑缺血再灌注介导的BBB损伤”的假说。阐明APN对GCIRI的作用与机制，为寻找早期减轻CA-CPR引起的BBB损伤提供新靶点。.