双环醇抑制大鼠矽肺纤维化的机制研究  

The mechanism of action of bicyclol on suppressing pulmonary fibrosis in silicotic rats

作　　者：詹芸 李瑞 王璐璐 蒋建东 韩燕星 ZHAN Yun;LI Rui;WANG Lu-lu;JIANG Jian-dong;HAN Yan-xing(State Key Laboratory of Bioactive Substances and Function of Natural Medicine,Institute of Materia Medica,Chinese Academy of Medical Sciences,Beijing 100050,China)

机构地区：[1]中国医学科学院药物研究所,天然药物活性物质与功能国家重点实验室,北京100050

出　　处：《中国新药杂志》2021年第18期1655-1660,共6页Chinese Journal of New Drugs

基　　金：国家“重大新药创制”科技重大专项资助项目(2018ZX09711001-011-003);中国医学科学院医学与健康科技创新工程资助项目(2020-I2M-1-003)。

摘　　要：目的:研究双环醇对大鼠矽肺纤维化的抑制作用,并对其作用机制进行了初步探讨。方法:采用气管滴注二氧化硅(silicon dioxide,SiO_(2))悬液的办法建立大鼠矽肺模型,通过对大鼠肺组织的苏木素-伊红(hematoxylin-eosin,HE)染色及Masson染色观察双环醇对肺纤维化的作用,通过免疫荧光(immunofluorescence,IF)和免疫组化(immunohistochemical,IHC)检测大鼠肺内巨噬细胞的活化及聚集情况,并用Western Blot方法在体外培养的细胞中进行验证。结果:气管滴注SiO_(2)28 d之后,HE染色显示大鼠肺组织中出现大量巨噬细胞聚集并形成大小不一的结节,证实大鼠矽肺模型的成功建立;给予矽肺大鼠双环醇治疗,HE染色和Masson染色结果表明,与对照组相比,双环醇组大鼠肺纤维化程度及肺内巨噬细胞的聚集程度均有明显减弱;IF和IHC染色结果表明双环醇组大鼠肺组织巨噬细胞中精氨酸酶1(arginase-1,Arg1)和诱导型一氧化氮合酶(inducible nitric oxide synthase,iNOS)的表达均明显降低;对体外培养的RAW264.7细胞进行SiO_(2)刺激然后给予双环醇处理,Western Blot结果表明双环醇同样能够抑制RAW264.7细胞中的Arg1和iNOS的表达。结论:双环醇可以通过下调巨噬细胞中Arg1和iNOS的表达,抑制巨噬细胞的聚集与活化,进而抑制大鼠矽肺纤维化进程,对尘肺治疗药物的探索具有潜在价值。Objective:To explored the inhibitory effect as well as the mechanism of bicyclol on pulmonary fibrosis in silicotic rats.Methods:A silicotic rat model was established by intratracheal drip of silicon dioxide(SiO_(2))suspension.Hematoxylin-eosin(HE)and Masson staining of rat lung tissues were performed for the exploration of the anti-fibrotic effect of bicyclol.Immunofluorescence(IF)and immunohistochemical(IHC)staining were used to observe macrophages aggregation and activation in rat lungs.Meanwhile,Western Blot assay was performed for further verification in cultured cells in vitro.Results:Both macrophage aggregation and nodule formation were observed in rat lungs by HE staining 28 days after intratracheal drip,indicating successful establishment of the silicotic rat model.Compared with the control group,both pulmonary fibrosis and macrophage aggregation in lungs of silicotic rats with bicyclol treatment were suppressed significantly using HE and Masson staining.IF and IHC staining showed downregulation of the expression of both arginase-1(Arg1)and inducible nitric oxide synthase(iNOS)in macrophages of silicotic rat lungs by bicyclol.Furthermore,inhibition of the expression of Arg1 and iNOS by bicyclol in RAW264.7 cells stimulated with SiO_(2)was observed using Western blot assay.Conclusion:Bicyclol suppresses macrophages aggregation and activation via down regulating Arg1 and iNOS,resulting in a slow-down of the process of pulmonary fibrosis in silicotic rats,which is likely to be a novel strategy for the treatment of silicosis.

关 键 词：双环醇 矽肺 肺纤维化 二氧化硅 巨噬细胞 

分 类 号：R965[医药卫生—药理学]