Toll样受体2介导博莱霉素诱导的急性肺损伤、炎症与纤维化(英文)  

Toll like receptor 2 mediates bleomycin-induced acute lung injury,inflammation and fibrosis in mice

作　　者：刘含智[1] 杨红振[1] 米粟[1] 崔冰[1] 花芳[1] 胡卓伟[1] 

机构地区：[1]中国医学科学院、北京协和医学院药物研究所分子免疫与分子药理实验室,北京100050

出　　处：《药学学报》2010年第8期976-986,共11页Acta Pharmaceutica Sinica

基　　金：supported by grants from the National Major Basic Research Program of China (973:#2006CB503808);the National Natural Science Foundation of China (30672468;30901814)

摘　　要：本文探讨TLR2是否介导博莱霉素(BLM)诱导的急性肺损伤、炎症与纤维化的发生。流式细胞术用于检测树突状细胞(DCs)成熟;ELISA方法检测细胞因子分泌;Western blotting检测蛋白表达与活化。小鼠气管内注入BLM制备急性肺损伤模型。结果表明,模型小鼠肺局部高表达TLR2(P<0.001)及其相关信号分子。阻断TLR2显著抑制BLM诱导的DCs成熟及细胞因子IL-6(P<0.001),IL-17(P<0.05)与IL-23(P<0.05)的分泌。阻断TLR2不仅抑制支气管肺泡灌洗液中炎性细胞的增加,而且还增强TH1(P<0.05),抑制TH2(P<0.001)、Treg(P<0.01)与TH17(P<0.01)反应。重要的是,阻断TLR2可显著减轻肺损伤、炎症与纤维化,提高动物的生存率(从50%到92%,P<0.01)。结果提示,TLR2可作为治疗急性肺损伤与肺纤维化的潜在药物靶点。Anti-cancer drug bleomycin （BLM） can cause acute lung injury （ALI） which often results in pulmonary fibrosis due to a failure of resolving acute inflammatory response. The aim of this study is to investigate whether toll-like receptor （TLR） 2 mediates BLM-induced ALI,inflammation and fibrosis. BLM-induced dendritic cells （DCs） maturation was analyzed by flow cytometry and cytokine secretion was detected by the ELISA method. The expression and activity of p38 and ERK MAPK were determined with Western blotting. The roles of TLR2 in ALI,inflammation and fibrosis were investigated in C57BL/6 mice administered intratracheally with BLM. The results demonstrated that BLM-administered mice had higher expression of TLR2 （P 0.001） and its signaling molecules. Blocking TLR2 significantly inhibited the maturation of DCs and reversed BLM-stimulated secretion of cytokines in DCs,such as IL-6 （P 0.001）,IL-17 （P 0.05） and IL-23 （P 0.05）. TLR2 inhibition attenuated BLM-induced increase of inflammatory cells in bronchoalveolar lavage fluid （BALF）,and reversed the immunosuppressive microenvironment by enhancing TH1 response （P 0.05） and inhibiting TH2 （P 0.001）,Treg （P 0.01） and TH17 （P 0.01） responses. Importantly,blocking TLR2 in vivo significantly protected BLM-administered mice from pulmonary injury,inflammation and fibrosis and subsequently increased BLM-induced animal survival （from 50% to 92%）. Therefore,TLR2 is a novel potential target for ALI and pulmonary fibrosis.

关 键 词：TLR2 博莱霉素 树突状细胞 肺部炎症 急性肺损伤 纤维化 

分 类 号：R963[医药卫生—微生物与生化药学]