甲磺司特通过抑制GATA3介导的Th2细胞分化治疗肺纤维化  

Suplatast tosilate attenuates pulmonary fibrosis by inhibiting the GATA3 induced Th2 differentiation

作　　者：刘畅[1,2] 刘姗姗 李云炫 花芳 吕晓希[1] LIU Chang;LIU Shan-shan;LI Yun-xuan;HUA Fang;Lü Xiao-xi(Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College.Beijing 100050,China;Drug Clinical Trial Institution,Children's Hospital,Capital Institute of Pediatrics,Beijing 100020,China;Institute of Medicinal Biotechnology,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 [2]首都儿科研究所附属儿童医院,北京100020 [3]中国医学科学院、北京协和医学院医药生物技术研究所,北京100050

出　　处：《药学学报》2021年第11期2977-2984,共8页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(82173875);中国医学科学院医学与健康科技创新工程项目(2021-1-I2M-026)。

摘　　要：肺纤维化是威胁人类健康的慢性呼吸系统炎性疾病。肺部组织局部的免疫微环境调控了纤维化疾病进程。本研究观察了甲磺司特抗肺纤维化疗效及其生物学机制。甲磺司特是辅助性T细胞2 (T helper 2, Th2)细胞因子抑制剂,用于临床支气管哮喘的治疗,但其是否能用于慢性肺纤维化的治疗及抑制Th2细胞因子释放的生物学机制并不清晰。通过体内及体外研究发现,甲磺斯特可以显著抑制多次博莱霉素损伤所致慢性肺纤维化发病,改善肺功能,减少肺部胶原沉积。同时甲磺司特通过抑制Th2细胞分化,显著减少Th2型细胞因子释放,但并不影响辅助性T细胞1 (T helper 1, Th1)细胞分化及Th1型细胞因子释放。进一步研究显示甲磺司特通过抑制信号传导及转录激活蛋白5 (signal transducer and activator of transcription 5, STAT5)及哺乳动物雷帕霉素靶标(mammalian target of rapamycin, mTOR)的磷酸化,下调GATA结合蛋白3 (GATA-binding protein 3, GATA3)的表达及活性抑制Th2细胞分化。肺部过表达GATA3可以翻转甲磺司特的抗肺纤维化疗效。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。本研究不仅阐释了甲磺司特的药理学作用机制,还为临床抗肺纤维化药物治疗提供了新的选择。Pulmonary fibrosis(PF) is a chronic respiratory inflammation disease that threatens human health.The topical immune microenvironment of lung tissue regulates progression of fibrosis. In this study, the efficacy and molecular mechanism of suplatast tosilate(ST) against PF were observed. ST is a T helper 2(Th2) cytokine inhibitor for clinical treatment of bronchial asthma. But whether it can be applied to therapy of chronic PF and the biomechanism of ST inhibiting Th2 cytokine release are not clear. Using in vivo and in vitro experiments, we found that ST can significantly suppress the pathogenesis of chronic PF induced by multiple bleomycin injury, improve the lung function, and decrease the deposition of collagen in lung tissue. In addition, ST decreases Th2 cytokine releasing through restraining Th2 cell differentiation in the meantime, but did not influence the T helper 1(Th1)cell differentiation and Th1 cytokine releasing. Further studies showed that ST inhibits Th2 cell differentiation by down-regulating GATA-binding protein 3(GATA3) expression and activity through inhibiting the phosphorylation of signal transducer and activator of transcription 5(STAT5) and mammalian target of rapamycin(mTOR). The excessive expression of GATA3 in lungs can reverse the anti-PF effect of ST. 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. Our research not only clarifies the pharmacological mechanism of ST, but also provides a new selection for clinical anti-PF drug therapy.

关 键 词：博莱霉素 免疫 细胞因子 TH2型细胞 呼吸系统炎性疾病 

分 类 号：R966[医药卫生—药理学]