曲美他嗪通过cGAS-STING通路对肺炎链球菌肺炎大鼠免疫功能的影响

Effect of trimetazidine on immune function in rats with Streptococcus pneumoniae pneumonia through cGAS-STING pathway

目的:探究曲美他嗪(TMZ)通过环鸟苷酸-腺苷酸合成酶(cGAS)-干扰素基因刺激蛋白(STING)通路对肺炎链球菌(SP)肺炎大鼠免疫功能的影响。方法:大鼠随机分为模型组、TMZ组、DMXAA组(cGAS-STING信号通路激活剂),鼻腔内滴入SP构建SP肺炎大鼠模型,对照组大鼠滴入等量生理盐水。ELISA检测IL-1β、IL-10水平;流式细胞术检测CD4^(+)T、CD8^(+)T细胞水平;比较各组大鼠脾脏、胸腺指数;透射比浊法检测IgG、IgA水平;HE染色观察肺组织病理变化;Western blot检测cGAS-STING通路蛋白表达。结果:与对照组比较,模型组大鼠肺泡壁和肺间质增厚,伴有水肿出血、炎症细胞浸润,IL-1β、CD8^(+)T细胞水平、肺组织病理损伤评分、cGAS、STING表达升高,IL-10、CD4^(+)T细胞、CD4^(+)T/CD8^(+)T、脾脏、胸腺指数、IgG、IgA水平降低(P<0.05);与模型组比较,TMZ组大鼠肺泡壁增厚减轻,肺泡结构显著改善、炎症细胞浸润较少,IL-1β、CD8^(+)T水平、肺组织病理损伤评分、cGAS、STING表达降低,IL-10、CD4^(+)T、CD4^(+)T/CD8^(+)T、脾脏、胸腺指数、IgG、IgA水平升高(P<0.05);与TMZ组比较,DMXAA组IL-1β、CD8^(+)T细胞水平、肺组织病理损伤评分、cGAS、STING表达升高,IL-10、CD4^(+)T细胞、CD4^(+)T/CD8^(+)T、脾脏、胸腺指数、IgG、IgA水平降低(P<0.05)。结论:TMZ可能通过抑制cGAS-STING信号通路激活抑制炎症,增强SP肺炎大鼠免疫功能。

Objective:To investigate effect of trimetazidine(TMZ)on immune function of Streptococcus pneumoniae(SP)pneumonia rats through cyclic guanylate adenylate synthase(cGAS)-stimulator of interferon gene(STING)pathway.Methods:Rats were randomly separated into model group,TMZ group and DMXAA group(cGAS-STING signaling pathway activator).SP pneumonia rat model was replicated by intranasal instillation of SP,while rats in control group were infused with an equal amount of physiological saline.ELISA was applied to detect IL-1βand IL-10 levels.Flow cytometry was applied to detect CD4^(+)T and CD8^(+)T levels.Spleen and thymus indexes of rats in each group were compared.Transmission turbidity method was applied to detect IgG and IgA levels.HE staining was applied to observe pathological changes in lung tissue.Western blot was applied to detect cGAS-STING pathway proteins expressions.Results:Compared with control group,rats in model group showed an increase in alveolar wall and lung interstitium,accompanied by edema,bleeding and inflammatory cell infiltration,IL-1β,CD8^(+)T cells levels,lung tissue pathological injury score,cGAS,STING expressions were increased,IL-10,CD4^(+)T cells levels,CD4^(+)T/CD8^(+)T,spleen and thymus indexes,IgG,IgA levels were decreased(P<0.05).Compared with model group,rats in TMZ group showed reduced thickening of alveolar walls,great improve-ment in alveolar structure,and less infiltration of inflammatory cells,IL-1β,CD8^(+)T cells levels,lung tissue pathological injury score,cGAS,STING expressions were decreased,IL-10,CD4^(+)T cells levels,CD4^(+)T/CD8^(+)T,spleen and thymus indexes,IgG,IgA levels were increased(P<0.05).Compared with TMZ group,IL-1β,CD8^(+)T levels,pathological injury score of lung tissue,cGAS and STING expressions in DMXAA group were increased,while IL-10,CD4^(+)T cells levels,CD4^(+)T/CD8^(+)T,spleen and thymus index,IgG and IgA levels were decreased(P<0.05).Conclusion:TMZ may inhibit inflammation by inhibiting cGAS-STING signaling pathway,and enhance immune function of rats with SP pneumonia.