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疏肝健脾方调控TLR4/MyD88/NLRP3信号轴抑制肝纤维化小鼠细胞焦亡的机制研究
引用本文:陈森,凡畅,张家富,马艳珍,姜辉.疏肝健脾方调控TLR4/MyD88/NLRP3信号轴抑制肝纤维化小鼠细胞焦亡的机制研究[J].金属学报,2022,27(10):1081-1089.
作者姓名:陈森  凡畅  张家富  马艳珍  姜辉
作者单位:安徽中医药大学第一附属医院 临床研究实验中心,合肥 230031,安徽
基金项目:国家自然科学基金项目(81973648)
摘    要:目的:基于TLR4/MyD88/NLRP3信号轴探究疏肝健脾方对肝纤维化小鼠的治疗作用及机制。方法:采用四氯化碳(CCl4)与橄榄油混合液背部皮下注射的方法,复制化学性肝纤维化小鼠模型。造模首日,灌胃给予疏肝健脾方,每天1次,连续12周;HE、Masson和天狼猩红染色观察小鼠肝组织病理学损伤程度,透射电镜观察肝组织超微结构的变化及焦亡小体情况;RT-qPCR、Western blot和免疫组织化学染色检测肝组织中α-SMA、Collagen Ⅰ、Caspase-1、IL-1β、IL-18以及TLR4/MyD88/NLRP3信号轴表达的变化情况。结果:病理分析显示模型组小鼠肝脏肝小叶结构模糊,肝细胞索排列紊乱,胶原沉积增加,焦亡小体数量明显增加,肝组织中α-SMA、Collagen Ⅰ、Caspase-1、IL-1β、IL-18以及TLR4、MyD88和NLRP3的mRNA和蛋白表达水平相较于正常组肝脏均显著升高。与模型组相比,疏肝健脾方给药后可改善肝脏病理组织学损伤程度,抑制细胞焦亡,显著下调α-SMA、Collagen Ⅰ、Caspase-1、IL-1β、IL-18以及TLR4、MyD88和NLRP3 mRNA与蛋白表达水平。 结论:疏肝健脾方抗肝纤维化作用可能与调控TLR4/MyD88/NLRP3信号轴,减少细胞焦亡,抑制肝星状细胞活化有关。

关 键 词:疏肝健脾方  肝纤维化  TLR4/MyD88/NLRP3信号轴  细胞焦亡  
收稿时间:2022-07-11
修稿时间:2022-08-22

The mechanism of Shugan Jianpi Formula regulating TLR4/MyD88/NLRP3 signaling axis to inhibit pyroptosis in mice with liver fibrosis
CHEN Sen,FAN Chang,ZHANG Jiafu,MA Yanzhen,JIANG Hui.The mechanism of Shugan Jianpi Formula regulating TLR4/MyD88/NLRP3 signaling axis to inhibit pyroptosis in mice with liver fibrosis[J].Acta Metallurgica Sinica,2022,27(10):1081-1089.
Authors:CHEN Sen  FAN Chang  ZHANG Jiafu  MA Yanzhen  JIANG Hui
Affiliation:Clinical Research Experiment Center, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei 230031, Anhui, China
Abstract:AIM: To explore the therapeutic effect and mechanism of Shugan Jianpi Formula on liver fibrosis mice based on TLR4/MyD88/NLRP3 signaling axis. METHODS: The chemical liver fibrosis mouse model was established by carbon tetrachloride (CCl4) mixed with olive oil. On the first day of modeling, the mice were gavage-administrated with Shugan Jianpi Formula once a day, for 12 weeks. The liver histopathology was observed by HE staining, Masson staining and Sirius red staining. The degree of injury, the ultrastructural changes of mouse liver tissue and the situation of pyroptosis were observed by transmission electron microscope. The expression changes of α-SMA, Collagen Ⅰ, Caspase-1, IL-1β, IL-18 and TLR4/MyD88/NLRP3 signaling axis were detected by RT-qPCR, Western blot and immunohistochemical staining. RESULTS: Pathological analysis showed that the structure of liver lobules in the model group was blurred, the arrangement of hepatocyte cords was disordered, the collagen deposition increased, and the number of pyroptotic bodies in liver cells increased significantly. The RNA and protein expression levels of α-SMA, Collagen Ⅰ, Caspase-1, IL-1β, IL-18, TLR4, MyD88 and NLRP3 were significantly higher than those in the normal group. Compared with the model group, the administration of Shugan Jianpi Formula could improve the degree of liver histopathological damage, inhibit cell pyroptosis, and significantly down-regulate the RNA and protein expression levels of α-SMA, Collagen Ⅰ, Caspase-1, IL-1β, IL-18, as well as TLR4, MyD88 and NLRP3 in liver tissue. CONCLUSION: The anti-fibrosis effect of Shugan Jianpi Formula may be related to the regulation of TLR4/MyD88/NLRP3 signaling axis, reduction of cell death and inhibition of hepatic stellate cell activation.
Keywords:Shugan Jianpi Formula  liver fibrosis  TLR4/MyD88/NLRP3 signaling axis  pyroptosis  
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