基于IL-33/ST2通路介导的小胶质细胞极化探讨参附黄配方对脓毒症认知功能障碍和突触可塑性的调节机制

脓毒症脑功能障碍是导致患者死亡率增高的重要原因。小胶质细胞（MG）极化介导的神经炎症反应是认知行为和突触可塑性改变的关键环节。脓毒症基本病机是正虚毒损、络脉闭阻，扶正解毒通络是主要治则。代表方参附黄配方有效，但其对脓毒症认知障碍的作用机制尚未知。白介素33（IL-33）与ST2结合可促进MG向抑炎M2型极化，改善认知。前期发现参附黄可增强脓毒症突触可塑性，减少MG激活，体外调节M1、M2型细胞因子分泌；固相芯片证实该方对IL-33上调最显著。本研究旨在结合行为学、电生理等技术明确参附黄对脓毒症认知障碍的疗效；检测该方对IL-33/ST2通路及MG极化的影响；应用基因敲除鼠和膜片钳技术开展体外研究明确该方对MG极化和神经元突触可塑性的作用机制；采用侧脑室注射及应用敲除鼠，明确抑制/激活IL-33/ST2通路对该方改善认知障碍和MG极化的影响。为阐明参附黄的分子机制，扩大临床应用提供理论依据。

The brain dysfunction of sepsis is an important cause of increased mortality. Microglia (MG) polarization mediated neuroinflammatory response plays a key role in dysfunctional cognitive behavior and synaptic plasticity. The basic pathogenesis of sepsis is deficiency and damage of toxin, blocking of collaterals, and s ‘strengthening healthy energy and detoxifying and dredging collaterals therapeutics’ is the principle of sepsis treatment. Shenfuhuang, a representative formula of this treatment principle, is effective in treating sepsis. However, its effect and mechanism on cognitive impairment of sepsis is unknown. The combination of interleukin 33 (IL-33) and ST2 promoted the polarization of MG to anti-inflammatory m2 phenotype and improved cognition. We found previously that Shenfuhuang formula could enhance the synaptic plasticity of sepsis, reduce the activation of MG, and regulate the secretion of M1 and M2 cytokines in vitro. The purpose of this study is to determine the effect of Shenfuhuang formula on cognitive impairment of sepsis by combining behavioral and electrophysiological techniques; to detect the effect of Shenfuhuang formula on IL-33 / ST2 pathway and Mg polarization; to study the mechanism of Shenfuhuang formula on MG polarization and neuronal synaptic plasticity by using knockout mice and patch clamp techniques in vitro; to determine the effect of Shenfuhuang formula on cognitive impairment and MG polarization while inhibited / activated IL-33 /ST2 pathway by injection into lateral ventricle or using knockout mice. This study provides theoretical basis for clarifying the molecular mechanism of Shenfuhuang formula and expanding its clinical application.