雷帕霉素对氮芥致小鼠肺纤维化的保护作用及机制  

Protective effect and mechanism of rapamycin on pulmonary fibrosis induced by Chlormethine in mice

作　　者：黄丽娟 杜冰 徐子瑛 袁静[1] Huang Lijuan;Du Bing;Xu Ziying;Yuan Jing(Capital Institute of Pediatrics,Beijing 100020,China)

机构地区：[1]首都儿科研究所细菌学研究室,北京100020

出　　处：《中华预防医学杂志》2024年第10期1573-1579,共7页Chinese Journal of Preventive Medicine

基　　金：北京市自然科学基金(7244288)。

摘　　要：探究雷帕霉素(RAPA)对氮芥诱导的C57BL/6N小鼠肺纤维化的治疗作用及机制。采用18~20 g C57BL/6N小鼠按照体重随机分为5组,分别是对照组、氮芥组、氮芥+地塞米松(1 mg/kg)组、氮芥+RAPA(1 mg/kg)组和氮芥+RAPA(2 mg/kg)组,每组10只。第一次给予氮芥后21 d处死小鼠。采用苏木精-伊红染色法和马松染色法观察肺组织病理结构变化和纤维化程度,采用RT-PCR技术检测可溶性胶原蛋白Ⅰ(collagenⅠ)、钙黏附蛋白(E-cadherin)、波形蛋白(vimentin)和α-肌动蛋白(α-SMA)的表达变化。通过氮芥+RAPA高剂量(2 mg/kg)组小鼠肺组织转录组数据分析,确定RAPA治疗氮芥诱导的肺纤维化的核心通路。结果显示,给予小鼠氮芥21 d后,小鼠肺组织出现明显的肺纤维化特征。与氮芥组比较,氮芥+地塞米松(1 mg/kg)组、氮芥+RAPA(1 mg/kg)组和氮芥+RAPA(2 mg/kg)组小鼠体重显著增加(P<0.05);氮芥+地塞米松(1 mg/kg)组、氮芥+RAPA(1 mg/kg)组和氮芥+RAPA高剂量(2 mg/kg)组纤维化相关指标collagenⅠ,E-cadherin,vimentin和α-SMA表达显著改善(P<0.05);与氮芥组比较,氮芥+地塞米松(1 mg/kg)组、氮芥+RAPA(1 mg/kg)组和氮芥+RAPA(2 mg/kg)组肺组织病理变化和胶原沉积情况明显改善。小鼠肺组织转录组数据分析显示,RAPA治疗氮芥诱导的肺纤维化可能与NF-kappa B信号通路有关。同时,RAPA组和地塞米松组小鼠的肺组织中NF-kappa B信号通路关键基因p65表达量显著下降(P<0.01)。综上,RAPA对氮芥诱导小鼠肺纤维化具有保护作用,其效果与临床上正在使用的地塞米松药效相当,是一种新的替代疗法,其机制可能与抑制NF-kappa B信号通路的激活相关。To evaluate the therapeutic effect and mechanism of rapamycin(RAPA)on pulmonary fibrosis induced by chlormethine in C57BL/6N mice.Based on body weight,the 18-20 g C57BL/6N mice were randomly divided into five groups:control group,chlormethine group,chlormethine+dexamethasone(1 mg/kg)group,chlormethine+RAPA(1 mg/kg)group and chlormethine+RAPA(2 mg/kg)group,with ten mice in each group.Mice were put to death on the 21st day after the first administration of chlormethine.HE staining and Masson staining were used to observe the pathological changes and degree of fibrosis in the lung tissue of mice,and RT-PCR was used to detect collagenⅠ,E-cadherin,vimentin,andα-SMA mRNA expression.After 21 days of administration of chlormethine to mice,significant pulmonary fibrosis characteristics were observed in the lung tissue of the mice.Compared with the chlormethine group,the weight of mice in the chlormethine+dexamethasone(1 mg/kg)group,chlormethine+RAPA(1 mg/kg)group and chlormethine+RAPA(2 mg/kg)group,significantly increased(P<0.05).Compared with the chlormethine group,the expression of pulmonary fibrosis-related indicators(collagenⅠ,E-cadherin,vimentin,andα-SMA)significantly improved(P<0.05)in the chlormethine+dexamethasone(1 mg/kg)group,chlormethine+RAPA(1 mg/kg)group and chlormethine+RAPA(2 mg/kg)group.Compared with the chlormethine group,the pathological changes and collagen deposition in the lung tissue of mice in the chlormethine+dexamethasone(1 mg/kg)group,chlormethine+RAPA(1 mg/kg)group and chlormethine+RAPA(2 mg/kg)group,were significantly improved.Transcriptome analysis of the lung tissue of mice revealed that RAPA treatment of chlormethine-induced pulmonary fibrosis might be related to NF-kappa B signaling pathway.Compared with the chlormethine group,the mRNA expression of p65 in the lung tissue of mice in the chlormethine+dexamethasone(1 mg/kg)group,chlormethine+RAPA(1 mg/kg)group and chlormethine+RAPA(2 mg/kg)group,significantly decreased(P<0.01).RAPA has a protective effect on pulmonary fibrosis induced b

关 键 词：肺纤维化 雷帕霉素 NF-kappa B信号通路 氮芥 

分 类 号：R563[医药卫生—呼吸系统]