吡非尼酮和尼达尼布抑制慢性肺纤维化小鼠肺泡上皮细胞再生  

Pirfenidone and nintedanib inhibit the lung alveolar regeneration in chronic pulmonary fibrosis mouse

作　　者：李云炫 吕晓希[1] 刘畅[1] 刘姗姗 胡卓伟[1] LI Yun-xuan;LüXiao-xi;LIU Chang;LIU Shan-shan;HU Zhuo-wei(Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China)

机构地区：[1]中国医学科学院、北京协和医学院药物研究所,北京100050

出　　处：《药学学报》2020年第5期861-867,共7页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(81530093);中国医学科学院医学与健康科技创新工程(2016-12M-1-008).

摘　　要：本研究探究了吡非尼酮(pirfenidone, Pirf)和尼达尼布(nintedanib, Nint)两种药物在单次及多次博莱霉素诱导的小鼠肺纤维化模型中,抗纤维化作用差异与肺泡Ⅱ型上皮细胞(alveolar epithelial type 2 cell, AEC Ⅱ)介导的肺泡再生之间的关系。本实验所有动物实验均通过中国医学科学院药物研究所伦理审查委员会审查。结果表明:在单次模型中, Pirf及Nint给药组小鼠的肺重指数显著降低,血氧饱和度显著回升,肺功能得到了明显改善,炎症评分显著降低,羟脯氨酸的含量显著下降,表明两种药物具有显著的抗纤维化作用;而在多次模型中两者均没有明显的抗纤维化作用。进一步研究表明Pirf和Nint能够降低β-catenin、Axin2、c-Myc和Cyclin D1蛋白的表达,抑制Wnt/β-catenin信号通路的活化,进而抑制AEC Ⅱ的干性功能。以上结果提示,在多次模型中, Pirf和Nint两种药物没有明显的抗纤维化作用是由于药物抑制Wnt/β-catenin信号通路导致AEC Ⅱ细胞的干性功能受阻,即AEC Ⅱ细胞介导的肺泡再生受到了抑制。The aim of this study was to determine whether the anti-fibrotic effects of pirfenidone(Pirf) and nintedanib(Nint) associated with the regulation of the alveolar epithelial type 2 cell(AEC Ⅱ)-mediated lung alveolar regeneration in single-and multiple-dosage animal models of bleomycin-induced pulmonary fibrosis. All procedures involving animal treatment were approved according to the Committee on the Ethics of Animal Experiments of the Institute of Materia Medica, Chinese Academy of Medical Sciences. We found that the Pirf and Nint treatment of mice decreased the lung weight index, inflammation level, and the content of hydroxyproline compared with nontreated fibrotic mice in the single dosage model. Also, Pirf and Nint increased the oxygen saturation level and improved the lung functions in fibrotic mice, indicating that both drugs have anti-fibrotic effects in this model.However, the anti-fibrotic effects of Pirf and Nint were not observed in the multiple-dosage model. Further studies showed that Pirf and Nint decreased the expression of β-catenin, Axin2, c-Myc, Cyclin D1, and inhibited the Wnt/β-catenin signaling pathway, suggesting that Pirf and Nint did not produce anti-fibrotic effects in the multipledosage model due to their inhibiting the Wnt/β-catenin pathway and suppressing the stemness of AEC Ⅱ, namely,suppressing AEC Ⅱ-mediated lung alveolar regeneration.

关 键 词：肺泡Ⅱ型上皮细胞 吡非尼酮 尼达尼布 肺纤维化 再生 

分 类 号：R966[医药卫生—药理学]