Pirfenidone ameliorates silica-induced lung inflammation and fibrosis in mice by inhibiting the secretion of interleukin-17A

被引:56
作者
Cao, Zhu-jie [1 ,2 ]
Liu, Ying [1 ,2 ]
Zhang, Zhe [3 ]
Yang, Pei-ran [1 ,2 ]
Li, Zhao-guo [4 ]
Song, Mei-yue [5 ,6 ,7 ,8 ,9 ]
Qi, Xian-mei [1 ,2 ]
Han, Zhi-fa [10 ]
Pang, Jun-ling [1 ,2 ]
Li, Bai-cun [1 ,2 ]
Zhang, Xin-ri [3 ]
Dai, Hua-ping [6 ,7 ,8 ,9 ]
Wang, Jing [1 ,11 ]
Wang, Chen [1 ,6 ,7 ,8 ,9 ]
机构
[1] Chinese Acad Med Sci, Inst Basic Med Sci, State Key Lab Med Mol Biol, Beijing 100005, Peoples R China
[2] Peking Union Med Coll, Dept Pathophysiol, Beijing 100005, Peoples R China
[3] Shanxi Med Univ, Dept Pulm & Crit Care Med, Hosp 1, Taiyuan 030001, Peoples R China
[4] Harbin Med Univ, Dept Resp, Affiliated Hosp 2, Harbin 150086, Peoples R China
[5] Beijing Univ Chinese Med, Beijing 100029, Peoples R China
[6] China Japan Friendship Hosp, Ctr Resp Med, Dept Pulm & Crit Care Med, Beijing 100029, Peoples R China
[7] Natl Ctr Resp Med, Beijing 100029, Peoples R China
[8] Chinese Acad Med Sci, Inst Resp Med, Beijing 100029, Peoples R China
[9] Natl Clin Res Ctr Resp Dis, Beijing 100029, Peoples R China
[10] Tsinghua Univ, Sch Med, Dept Basic Med Sci, Beijing 100084, Peoples R China
[11] Shanxi Med Univ, Key Lab Cellular Physiol, Minist Educ, Taiyuan 030012, Peoples R China
基金
中国国家自然科学基金;
关键词
silicosis; pirfenidone; interleukin-17A; inflammation; fibrosis; PULMONARY-FIBROSIS; IL-17; DISEASE; CELLS;
D O I
10.1038/s41401-021-00706-4
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Silicosis is a global occupational disease characterized by lung dysfunction, pulmonary inflammation, and fibrosis, for which there is a lack of effective drugs. Pirfenidone has been shown to exert anti-inflammatory and anti-fibrotic properties in the lung. However, whether and how pirfenidone is effective against silicosis remains unknown. Here, we evaluated the efficacy of pirfenidone in the treatment of early and advanced silicosis in an experimental mouse model and explored its potential pharmacological mechanisms. We found that pirfenidone alleviated silica-induced lung dysfunction, secretion of inflammatory cytokines (TNF-alpha, IL-1 beta, IL-6) and deposition of fibrotic proteins (collagen I and fibronectin) in both early and advanced silicosis models. Moreover, we observed that both 100 and 200 mg/kg pirfenidone can effectively treat early-stage silicosis, while 400 mg/kg was recommended for advanced silicosis. Mechanistically, antibody array and bioinformatic analysis showed that the pathways related to IL-17 secretion, including JAK-STAT pathway, Th17 differentiation, and IL-17 pathway, might be involved in the treatment of silicosis by pirfenidone. Further in vivo experiments confirmed that pirfenidone reduced the production of IL-17A induced by silica exposure via inhibiting STAT3 phosphorylation. Neutralizing IL-17A by anti-IL-17A antibody improved lung function and reduced pulmonary inflammation and fibrosis in silicosis animals. Collectively, our study has demonstrated that pirfenidone effectively ameliorated silica-induced lung dysfunction, pulmonary inflammation and fibrosis in mouse models by inhibiting the secretion of IL-17A.
引用
收藏
页码:908 / 918
页数:11
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