【摘要】 目的 探究人脐带来源的间充质干细胞（hUCMSCs）调节GMP-AMP合酶-干扰素基因刺激物-核转录因子-κB(cGAS-STING-NF-κB)信号通路对慢性间歇缺氧（CIH）小鼠的干预价值。方法 24只C57BL/6小鼠分为对照组、模型组、hUCMSCs组和hUCMSCs+STING激活剂（DMXAA）组，每组6只。除对照组外，其余各组置于低氧舱中每日8 h共8周制备CIH小鼠模型。8周后，将小鼠麻醉后取心尖血，随后处死各组小鼠，收集肺组织。酶联免疫吸附试验检测血清白细胞介素（IL）-6、IL-1β、肿瘤坏死因子-α(TNF-α)、IL-17A水平，根据苏木素-伊红（HE）染色和马松（Masson）染色结果进行炎症评分和纤维化评分，免疫组化染色检测E钙黏蛋白（E-Cadherin）、α平滑肌肌动蛋白（α-SMA）表达情况，RT-qPCR检测cGAS、STING、NF-κB mRNA表达水平，免疫印迹实验检测E-Cadherin、N钙黏蛋白（N-Cadherin）、波形蛋白（Vimentin）、cGAS、NF-κB、α-SMA、STING蛋白表达水平。结果 与对照组相比，模型组IL-6、IL-1β、TNF-α、IL-17A水平升高，炎症评分和纤维化评分升高，cGAS、STING、NF-κB mRNA表达水平升高，N-Cadherin、α-SMA、Vimentin、cGAS、STING、NF-κB蛋白表达水平升高；E-Cadherin蛋白表达水平降低（P<0.05）。与模型组相比，hUCMSCs组IL-6、IL-1β、TNF-α、IL-17A水平降低，cGAS、STING、NF-κB mRNA表达水平降低，N-Cadherin、α-SMA、Vimentin、cGAS、STING、NF-κB蛋白表达水平降低；E-Cadherin蛋白表达水平升高（P<0.05）。STING激活剂DMXAA逆转了hUCMSCs对CIH小鼠的保护作用（P<0.05）。结论 经尾静脉注射hUCMSCs可减轻间歇低氧小鼠的肺组织炎症浸润及上皮间充质转化，可能与cGAS-STING-NF-κB信号通路下调有关。更多还原

【Abstract】 Objective To investigate the therapeutic potential of human umbilical cord-derived mesenchymal stem cells(hUCMSCs) in modulating the cGAS-STING-NF-κB signaling pathway in chronic intermittent hypoxia(CIH) mice.Methods Twenty-four C57BL/6 mice were divided into the control group, the model group, the hUCMSCs group and the hUCMSCs+STING agonist(DMXAA) group, with 6 mice in each group. Except for the control group, the other groups were exposed to hypoxic conditions for 8 hours daily for a total of 8 weeks to establish the CIH mouse model. After 8 weeks, mice were anesthetized for cardiac blood collection followed by euthanasia and lung tissue collection. Serum levels of IL-6, TNF-α, IL-1β and IL-17A were measured by ELISA. Pulmonary inflammatory infiltration and collagen deposition were assessed by HE and Masson staining. E-Cadherin and α-SMA expression levels were evaluated by immunohistochemistry. Expression levels of cGAS, STING and NF-κB mRNA were detected by RT-qPCR, while protein expression levels of E-Cadherin, NCadherin, α-SMA, Vimentin, cGAS, STING and NF-κB were analyzed by Western blot assay. Results Compared with the control group, levels of IL-6, IL-1β, TNF-α and IL-17A increased in the model group, inflammation and fibrosis scores increased, mRNA expression levels of cGAS, STING and NF-κB increased, and protein expression levels of N-Cadherin,α-SMA, Vimentin, cGAS, STING and NF-κB increased. In contrast, E-Cadherin protein expression was significantly decreased(P<0.05). Compared with the model group, IL-6, IL-1β, TNF-α and IL-17A decreased in the hUCMSCs group,mRNA expression levels of cGAS, STING and NF-κB were decreased, protein expression levels of N-Cadherin, α-SMA,Vimentin, cGAS, STING and NF-κB were also decreased. Meanwhile, E-Cadherin protein expression was significantly increased(P<0.05). STING activator DMXAA reversed the protective effects of hUCMSCs in CIH mice(P<0.05).Conclusion Intravenous administration of hUCMSCs alleviates pulmonary inflammatory infiltration and epithelialmesenchymal transition in mouse model of intermittent hypoxia, which may be related to the down-regulation of the cGASSTING-NF-κBsignaling pathway.更多还原