Toll like receptor 2 mediates bleomycin-induced acute lung injury, inflammation and fibrosis in mice.
- Author:
Han-zhi LIU
1
;
Hong-zhen YANG
;
Su MI
;
Bing CUI
;
Fang HUA
;
Zhuo-wei HU
Author Information
1. Molecular Immunology and Pharmacology Laboratory, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
- Publication Type:Journal Article
- MeSH:
Acute Lung Injury;
chemically induced;
metabolism;
pathology;
Animals;
Bleomycin;
toxicity;
Bronchoalveolar Lavage Fluid;
Cells, Cultured;
Cytokines;
secretion;
Dendritic Cells;
cytology;
metabolism;
Inflammation;
chemically induced;
metabolism;
pathology;
Interleukin-17;
secretion;
Interleukin-23;
secretion;
Interleukin-6;
secretion;
Lung;
metabolism;
MAP Kinase Signaling System;
Male;
Mice;
Mice, Inbred C57BL;
Pulmonary Fibrosis;
chemically induced;
metabolism;
pathology;
T-Lymphocytes, Regulatory;
drug effects;
Th1 Cells;
drug effects;
Th2 Cells;
drug effects;
Toll-Like Receptor 2;
metabolism;
physiology
- From:
Acta Pharmaceutica Sinica
2010;45(8):976-986
- CountryChina
- Language:English
-
Abstract:
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.
