【摘要】 目的 探讨右美托咪定（DEX）通过环磷酸鸟苷-腺苷酸合成酶-干扰素基因刺激因子（cGAS-STING）通路抑制大鼠创伤性脑损伤（TBI）后小胶质细胞介导的炎症反应。方法 构建TBI大鼠模型，将造模成功大鼠随机抽样分为TBI组、右美托咪定低、高剂量处理组（DEX-L、DEX-H组）、右美托咪定高剂量处理+cGAS-STING通路激活剂组（DEX-H+DMXAA组），每组18只，另取18只健康正常大鼠作为对照组（Control组）；对各组大鼠进行神经行为学评分（mNSS）；检测各组大鼠脑组织脑水含量；流式细胞术检测各组大鼠脑组织中Tregs数量；ELISA检测脑组织炎症因子水平；HE染色观察脑组织损伤；TUNEL染色检测神经元凋亡；免疫组化检测小胶质细胞标志物离子钙结合衔接分子1(Iba1)表达；Westem blot检测凋亡及cGASSTING通路相关蛋白表达。结果 TBI组较Control组脑组织结构破坏，出现水肿，神经元形态异常，数量减少且排列紊乱，核皱缩深染，核仁模糊；mNSS评分，脑组织含水量，Tregs、TNF-α、IL-1β、IL-6水平及神经元凋亡率、C-caspase-3、caspase-3、Iba1、cGAS、p-STING、p-TBK1、p-IRF3、IFN-Ⅰ表达水平升高（P<0.05）;DEX-L、DEX-H组较TBI组脑组织结构轻度破坏，水肿减轻，神经元形态相对正常，数量少量减少，排列相对整齐，少量核皱缩深染，核仁大部分明显；mNSS评分，脑组织含水量，Tregs、TNF-α、IL-1β、IL-6水平及神经元凋亡率、C-caspase-3、caspase-3、Iba1、cGAS、p-STING、p-TBK1、p-IRF3、IFN-Ⅰ表达水平降低（P<0.05）;DEX-H+DMXAA组较DEX-H组脑组织结构及神经元损伤严重，mNSS评分，脑组织含水量，Tregs、TNF-α、IL-1β、IL-6水平及神经元凋亡率、C-caspase-3、caspase-3、Iba1、c GAS、p-STING、p-TBK1、p-IRF3、IFN-Ⅰ表达水平升高（P<0.05）。结论 右美托咪定可抑制大鼠TBI后小胶质细胞介导的炎症反应，其作用机制与抑制c GAS-STING通路相关。更多还原

【Abstract】 Objective To investigate whether dexmedetomidine(DEX) can inhibit the inflammatory response mediated by microglia after traumatic brain injury(TBI) in rats through the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon gene(cGAS-STING) pathway. Methods A TBI rat model was constructed, and successfully modeled rats were randomly separated into TBI group, low and high-dose dexmedetomidine treatment groups(DEX-L, DEX-H groups), and high-dose dexmedetomidine treatment+cGAS-STING pathway activator group(DEX-H+DMXAA group), with 18 rats in each group. Additionally, 18 healthy normal rats were selected as the Control group. Rats in each group were subjected to neurobehavioral scoring(mNSS). The brain water content of rats in each group was detected. Flow cytometry was used to detect Tregs in the brain tissue of each group. ELISA was applied to detect the levels of inflammatory cytokines in brain tissue. HE staining was applied to observe brain tissue injury. TUNEL staining was applied to detect neuronal apoptosis. Immunohistochemistry was applied to detect the expression of the microglial cell marker ion calcium binding adapter molecule 1(Iba1). Western blot was applied to detect the expression of apoptosis and cGAS-STING pathway related proteins. Results Compared with the Control group, the TBI group showed structural injury to brain tissue, edema, abnormal neuronal morphology, reduced number and disordered arrangement, deep staining of nuclear folds, and blurred nucleoli, the mNSS score, brain tissue water content, levels of Tregs, TNF-α, IL-1β, IL-6, neuronal apoptosis rate, expression of caspase-3, caspase-3, Iba1, cGAS, p-STING, p-TBK1, p-IRF3, IFN-Ⅰ were elevated(P<0.05). Compared with the TBI group, the brain tissue structure of the DEX-L and DEX-H groups was slightly injuried, edema was reduced, and the morphology of neurons was relatively normal, with a small decrease in number and relatively neat arrangement, a small amount of nuclei were wrinkled and deeply stained, and most of the nucleoli were obvious, the mNSS score, brain tissue water content, levels of Tregs, TNF-α, IL-1β, IL-6, neuronal apoptosis rate, expression of caspase-3, caspase-3, Iba1, cGAS, p-STING, p-TBK1, p-IRF3, IFN-Ⅰ were reduced(P<0.05). The brain tissue structure and neuronal injury in the DEX-H+DMXAA group were more severe than the DEX-H group, the mNSS score, brain tissue water content, levels of Tregs, TNF-α, IL-1β, IL-6, neuronal apoptosis rate, expression of caspase-3, caspase-3, Iba1, cGAS, p-STING, p-TBK1, p-IRF3, IFN-Ⅰ were elevated(P<0.05). Conclusion Dexmedetomidine can inhibit the inflammatory response mediated by microglia after TBI in rats, and its mechanism of action is related to the inhibition of the cGAS-STING pathway.更多还原