摘要
目的 心脏骤停心肺复苏（cardiac arrest and cardiopulmonary resuscitation, CA/CPR)后的免疫抑制导致幸存患者更容易遭受感染，是导致患者院内感染和死亡的重要原因。然而，目前尚不清楚 CA/CPR后免疫抑制的具体机制。方法 我们评估了心肺复苏后小鼠的免疫功能和复苏后结果。通过干预膈下迷走神经和脾脏Sonic Hedgehog（SHH）信号通路，我们探索了迷走神经在免疫功能调控中的作用以及相关分子机制。我们对小鼠进行了膈下迷走神经离断术（subdiaphragmatic vagotomy, SDV）和SHH信号通路抑制剂干预，并系统评估了两者对免疫细胞亚群和细胞因子的影响。结果 心肺复苏后的免疫抑制表现为脾脏中 CD8+ T细胞亚群减少和髓源抑制性细胞（myeloid-derived suppressor cells, MDSCs）增加，以及血浆中白介素-10（IL-10）和转化生长因子-β (TGF-β) 水平升高。此外，SDV减轻了心脏骤停后出现的免疫抑制。心肺复苏后小鼠的脾脏蛋白免疫印迹结果显示SHH信号通路的显著上调，而SHH抑制剂的使用改善了小鼠的免疫抑制。结论 调节膈下迷走神经和SHH信号通路可改善全身免疫抑制并改善心肺复苏后的结果。我们的研究揭示了一种具有潜在临床意义的新治疗策略。
关键词： 心脏骤停和心肺复苏；免疫抑制；Sonic hedgehog；迷走神经；T淋巴细胞
Abstract
Objective Immunosuppression following cardiac arrest and cardiopulmonary resuscitation (CA/CPR) is linked to poor patient survival and susceptibility. However, the specific mechanisms of immunosuppression after CA/CPR remain unclear. Methods We evaluated immune function and post-resuscitation outcomes in CA/CPR mice. By modulating the subdiaphragmatic vagus nerve and splenic sonic hedgehog (SHH) signaling pathway, we explored the role of vagus nerve in immune regulation and its underlying molecular mechanisms. Mice were subjected to subdiaphragmatic vagotomy (SDV) and treatment with an SHH signaling inhibitor, and the effects of these interventions on immune cell subsets and cytokine profiles were systematically evaluated. Results Post-CA/CPR immunosuppression manifested as decreased CD8+ T cell subsets and increased myeloid-derived suppressor cells (MDSCs) in the spleen, along with elevated plasma interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β) levels. Furthermore, SDV mitigated the severity of immunosuppression after CA/CPR. Mechanistically, CA/CPR mice exhibited an up-regulation of the splenic SHH signaling pathway, and administration of an SHH inhibitor alleviated immunosuppression in CA/CPR mice. Conclusion Modulating subdiaphragmatic vagus nerve activity and SHH signaling alleviated immunosuppression and improved the outcomes post-CA/CPR. Our findings unveil a novel treatment strategy with potential clinical implications.
Key words： Cardiac arrest and cardiopulmonary resuscitation; Immunosuppression; Sonic hedgehog; Subdiaphragmatic vagus nerve; T cells
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