Abstract：
This study investigated the impact of two-hit inflammation on postoperative cognitive dysfunction (POCD) in mice and the role of macrophage-derived exosomes in regulating this process. Mice models were used to mimic the state of two-hit inflammation, and cognitive function was assessed through behavioral experiments. Proinflammatory cytokine expression levels and blood-brain barrier (BBB)-associated functional proteins were measured using ELISA and Western blot, respectively. An in vitro macrophage inflammation two-hit model was created, and the role of exosomes was examined using the previously mentioned assays. Additionally, exosomes were injected into mice to further understand their impact in the two-hit inflammation model. Mice exposed to two-hit inflammation experienced impaired cognitive function, increased BBB permeability, and elevated levels of proinflammatory cytokines. Macrophages subjected to two-hit inflammation released higher levels of proinflammatory cytokines compared to the control group and other treatment groups. Treatment with an exosome inhibitor GW4869 effectively reduced the expression levels of proinflammatory cytokines in macrophages exposed to two-hit inflammation. Moreover, injection of macrophage-released exosomes into healthy mice induced inflammation, hippocampal damage, and cognitive disorders, which were mitigated by treatment with GW4869. In mice with two-hit inflammation, macrophage-released exosomes worsened cognitive disorders by promoting inflammation in the peripheral blood and central nervous system. However, treatment with GW4869 protected cognitive function by suppressing exosome release. These findings highlight the importance of two-hit inflammation in POCD and emphasize the critical role of exosomes as regulatory factors. This research provides valuable insights into the pathogenesis of POCD and potential intervention strategies.
摘要：
这项研究调查了双重炎症对小鼠术后认知功能障碍（POCD）的影响以及巨噬细胞衍生的外泌体在调节该过程中的作用。使用小鼠模型来模拟两次发作的炎症状态，认知功能通过行为实验进行评估。使用ELISA和Westernblot检测促炎细胞因子表达水平和血脑屏障（BBB）相关功能蛋白，分别。建立了体外巨噬细胞炎症两击模型，和外泌体的作用检查使用前面提到的测定。此外,将外泌体注射到小鼠体内,以进一步了解其在二次炎症模型中的影响.暴露于二次炎症的小鼠经历了认知功能受损，增加BBB通透性，和促炎细胞因子水平升高。与对照组和其他治疗组相比，遭受两次炎症的巨噬细胞释放更高水平的促炎细胞因子。用外泌体抑制剂GW4869治疗有效地降低了暴露于二次炎症的巨噬细胞中促炎细胞因子的表达水平。此外，向健康小鼠注射巨噬细胞释放的外泌体诱导的炎症，海马损伤,和认知障碍，通过GW4869治疗得到缓解。在患有两次炎症的小鼠中，巨噬细胞释放的外泌体通过促进外周血和中枢神经系统的炎症而使认知障碍恶化。然而,GW4869治疗通过抑制外泌体释放保护认知功能。这些发现强调了双重炎症在POCD中的重要性，并强调了外泌体作为调节因子的关键作用。这项研究为POCD的发病机制和潜在的干预策略提供了有价值的见解。
