延迟远隔缺血后处理通过胆碱能抗炎通路减轻心肺复苏脑损伤的机制研究

Treatment of global cerebral injury after cardiopulmonary resuscitation (CPR) is a difficult medical problem urgently to be solved. We firstly reported that delayed remote ischemic postconditioning (DRIPost) could alleviate cerebral injury after CPR in the asphyxial cardiac arrest (CA) rat model. In the preliminary experiments we observed that DRIPost could reduce the levels of inflammatory cytokines and increase the concentration of ACh in hippocampus and serum after CPR. Therefore, it is conjectured that the neuroprotection of DRIPost may have closely relationship with inhibiting inflammatory response. However, the regulation of DRIPost on the inflammatory response after CPR is still unclear. According to the studies of neural mechanism of remote ischemic conditioning （RIC）and our preliminary results, we believed that the cholinergic anti-inflammatory pathway mediated by the vagus nerve would play a critical role in the process of DRIPost alleviating cerebral injury after CPR. Based on the previous studies, we are going to further investigate the effects and mechanisms of DRIPost-induced neuroprotection, and the study is mainly focused on the vagus nerve-mediated cholinergic anti-inflammatory pathway, which includes the downstream α7nAChR-modulated NF-κB and JAK2/STAT3 pathway. This project will not only explore new therapeutic approaches and ideas for the global cerebral injury after CPR, and provide the theoretical support for DRIPost-induced neuroprotection, but also lead to novel targets for developing neuroprotective drugs via the modulation of neuroinflammtion.

防治心肺复苏脑损伤是亟待解决的一个医学难题。我们研究发现延迟远隔缺血后处理（DRIPost）能够减轻大鼠窒息性心肺复苏脑损伤，还能够降低心肺复苏后海马部位和血液中炎性因子的水平，升高乙酰胆碱水平，提示DRIPost的脑保护作用与抑制炎症反应有关，但DRIPost如何调控心肺复苏后的炎症反应尚不清楚。根据有关远隔缺血处理神经传导机制的研究以及本项目组初步的实验结果，我们推测迷走神经介导的胆碱能抗炎通路在DRIPost减轻心肺复苏脑损伤的过程中扮演重要角色。本项目拟在前期研究的基础上，利用在体和离体模型，研究DRIPost通过迷走神经介导的胆碱能抗炎通路及其下游α7nAChR调控的NF-κB和JAK2/STAT3通路减轻心肺复苏脑损伤的分子机制。为心肺复苏脑损伤探索新的治疗途径和思路，为DRIPost的脑保护作用提供新的理论依据，更为研发调控神经炎症发挥脑保护作用的药物提供新的靶点。

脑损伤是心肺复苏后严重并发症之一，而如何减少复苏后的神经系统并发症及提高生存率是一个亟待解决的临床医学问题，也是目前研究热点。作为一种新近被发现的缺血再灌注损伤保护策略，远隔缺血后处理（RIPost）引起研究人员的浓厚兴趣，但其具体保护机制尚未阐明。目前认为炎性反应是心脏骤停后脑损伤的重要原因之一，多种证据提示远隔缺血后处理与炎性反应息息相关。本课题组主要研究远隔缺血后处理对心肺复苏后脑损伤的保护作用及其相关炎性机制。我们提出假设：远隔缺血后处理通过迷走神经激动胆碱能抗炎通路，活化免疫细胞上的α7nAChR，进而通过阻断NF-κB活化、激活JAK2 / STAT3通路，减少炎症因子的合成和释放，减轻脑损伤。. 此项目开展以来，研究基本按照原计划执行，一些研究内容稍作调整。课题组主要研究内容包括：（1）建立窒息性心脏骤停模型；（2）发现RIPost明显减轻心肺复苏后脑炎症反应，减轻脑损伤；（3）发现RIPost增加脑Ach含量及α7nAChR表达量；（4）发现迷走神经的完整性在RIPost减轻大鼠心肺复苏后脑损伤中具有重要意义；（5）α7nAChR激动剂PHA-543613后处理可减轻心肺复苏后脑损伤；（6）神经元和小胶质细胞表面α7nAChR可调控氧糖剥夺后炎症反应减轻神经元损伤；（7）明确α7nAChR是RIPost产生脑保护作用的关键靶点，其通过阻断NF-κB活化、激活JAK2 / STAT3通路发挥作用。