γ-促分泌酶抑制剂对毛细支气管炎模型大鼠体内 Th17细胞分化的影响

摘要

Objective:To investigate the affection to the differentiation of Th17 cell in rat models of bronchiolitis after blocking Notch signaling by γ-secretase inhibitor and provide rationale to seek new target for bronchiolitis drug treatment. Methods:The rats were randomly divided into normal group,bronchiolitis group andγ-secretase inhibitor group. The model of bronchiolitis was established successfully by nasal dripping,and γ-secretase inhibitor(MW167) was injected into the vena caudalis. The pathological changes of the airway were observed by HE staining;the plasma level of interleukin17 ( IL-17 ) was detected by ELISA;the level of RORγt mRNA in lung tissues and peripheral blood mononuclear cells( PBMCs) was tested by real-time quantitative PCR;the levels of Notch signaling and RORγt protein in lung tissues were examined by Western blot. Results:Compared to the bronchiolitis group, the histopathologic change in MW167 intravenous injection group was significantly alleviated;the plasma level of IL-17 was decreased;the level of RORγt mRNA in lung tissues and PBMCs was lower in MW167-treated group than bronchiolitis group;the levels of Notch signaling and RORγt were decreased. Conclusion:γ-secretase inhibitor through intravenous injection suppresses the differentiation of Th17 cell and relieves the airway inflammation of bronchiolitis in rat models after blocking Notch signaling and has potential therapeutic value for treating bron-chiolitis.%目的：：研究γ-促分泌酶抑制剂阻断Notch信号对毛细支气管炎(简称毛支)模型大鼠Th17细胞发育和分化的影响,为毛支治疗寻找新的药物提供理论基础。方法：按随机对照原则将SD大鼠分为正常组、毛支组和γ-促分泌酶抑制剂组,滴鼻法成功建立毛支模型,而后尾静脉注射γ-促分泌酶抑制剂MW167,通过HE染色观察肺组织病理改变,ELISA检测血浆中白介素17(IL-17)的水平,实时荧光定量PCR检测肺组织和外周血单个核细胞中RORγt mRNA的表达,Western blot检测肺组织中Notch信号、RORγt的蛋白表达。结果：与毛支组相比,MW167组肺组织病理学改变减轻；血浆IL-17水平也较毛支组降低；肺组织及外周血单个核细胞RORγt mRNA在MW167注射组表达均减弱；MW167组肺组织Notch信号和RORγt蛋白的表达也显著降低。结论：静脉注射γ-促分泌酶抑制剂能够通过阻断Notch信号通路抑制Th17细胞的分化,缓解毛支模型大鼠的气道炎症,对毛支有潜在的治疗价值。