Department of Anesthesia, Postgraduate Training Base of Jinzhou Medical University in the General Hospital of Northern Theater Command, Shenyang 110016, China.
Department of Anesthesia, General Hospital of Northern Theater Command, Shenyang 110016, Liaoning, China.
J Healthc Eng. 2021 Oct 1;2021:3048383. doi: 10.1155/2021/3048383. eCollection 2021.
Cardiopulmonary bypass (CPB) is mainly used during cardiac surgeries that treat ischemic, valvular, or congenital heart disease and aortic dissections. The disorders of central nervous system (CNS) that occur after cardiopulmonary bypass are attracting considerable interest. Postoperative neurocognitive disorders (PND) have been reported as the leading cause of patients' disability and death following CPB. The -opioid receptor (KOR) agonists (U50488H) have been suggested to be vital in the treatment of surgically induced CNS neuroinflammatory responses. In this article, the transitions between the M1 and M2 microglial polarization state phenotypes were hypothesized to significantly affect the regulatory mechanisms of KOR agonists on postcardiopulmonary bypass (post-CPB) neuroinflammation. We investigated the effects of U50488H on neuroinflammation and microglia polarization in rats exposed to CPB and explored the method of the NLRP3/caspase-1 pathway. Thirty SD rats were randomly divided into three groups: sham operation group, cardiopulmonary bypass model group, and CPB+ -opioid receptor agonist (U50488H) group, with ten rats in each group. The Morris water maze was used to evaluate the changes in the cognitive function of CPB rats. Hematoxylin and eosin (HE) staining and TUNEL were performed to assess the rats' hippocampal damage. Enzyme-Linked Immunosorbent Assay (ELISA) was used to detect changes in brain injury markers and inflammatory factors. Furthermore, immunofluorescence was used to observe the expression of microglia polarization and NLRP3 followed by Western blots to detect the expression of the NLRP3/caspase-1 pathway and microglia polarization-related proteins. Rat microglia were cultured i, with LPS stimulation, and treated with U50488H and a caspase-1 antagonist to evaluate the effects and mechanism of action of U50488H. KORs alleviated hippocampal damage caused by CPB and improved PND. CPB activated the NLRP3 inflammasome and upregulated pro-caspase-1 expression which promoted the expression of pro-IL-l and pro-IL-18 and resulted in increased inflammation. However, KORs also inhibited NLRP3 and transformed microglia from the M1 to the M2 state. Caspase-1 inhibitor treatment reduced the microglial polarization induced by KORs. The -opioid receptor agonists inhibited the inflammation mediated by microglia and improved PND through the NLRP3/caspase-1 signaling pathway.
体外循环（CPB）主要用于治疗缺血性、瓣膜性或先天性心脏病和主动脉夹层的心脏手术。体外循环后中枢神经系统（CNS）的紊乱引起了相当大的关注。术后神经认知障碍（PND）被报道为 CPB 后患者残疾和死亡的主要原因。-阿片受体（KOR）激动剂（U50488H）已被证明对治疗手术引起的中枢神经系统神经炎症反应至关重要。在本文中，假设 M1 和 M2 小胶质细胞极化状态表型之间的转变将显著影响 KOR 激动剂对体外循环后（post-CPB）神经炎症的调节机制。我们研究了 U50488H 对 CPB 暴露大鼠神经炎症和小胶质细胞极化的影响，并探讨了 NLRP3/caspase-1 途径的方法。30 只 SD 大鼠随机分为三组：假手术组、体外循环模型组和 CPB+ -阿片受体激动剂（U50488H）组，每组 10 只。使用 Morris 水迷宫评估 CPB 大鼠认知功能的变化。苏木精和伊红（HE）染色和 TUNEL 用于评估大鼠海马损伤。酶联免疫吸附试验（ELISA）用于检测脑损伤标志物和炎症因子的变化。此外，免疫荧光观察小胶质细胞极化和 NLRP3 的表达，然后进行 Western blot 检测 NLRP3/caspase-1 通路和小胶质细胞极化相关蛋白的表达。用 LPS 刺激培养大鼠小胶质细胞，并给予 U50488H 和 caspase-1 拮抗剂，以评估 U50488H 的作用和作用机制。KOR 减轻 CPB 引起的海马损伤并改善 PND。CPB 激活 NLRP3 炎性小体，上调前胱天蛋白酶-1 的表达，促进前 IL-1 和前 IL-18 的表达，导致炎症增加。然而，KOR 还抑制 NLRP3 并将小胶质细胞从 M1 转化为 M2 状态。Caspase-1 抑制剂治疗减少了 KOR 诱导的小胶质细胞极化。-阿片受体激动剂通过 NLRP3/caspase-1 信号通路抑制小胶质细胞介导的炎症，改善 PND。
