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

作　　者：Zhu-jie Cao Ying Liu Zhe Zhang Pei-ran Yang Zhao-guo Li Mei-yue Song Xian-mei Qi Zhi-fa Han Jun-ling Pang Bai-cun Li Xin-ri Zhang Hua-ping Dai Jing Wang Chen Wang 

机构地区：[1]State Key Laboratory of Medical Molecular Biology,Institute of Basic Medical Sciences,Chinese Academy of Medical Sciences,Beijing,100005,China [2]Department of Pathophysiology,Peking Union Medical College,Beijing,100005,China [3]Department of Pulmonary and Critical Care Medicine,the First Hospital of Shanxi Medical University,Taiyuan,030001,China [4]Department of Respiratory,the Second Affiliated Hospital of Harbin Medical University,Harbin,150086,China [5]Beijing University of Chinese Medicine,Beijing,100029,China [6]Department of Pulmonary and Critical Care Medicine,Center of Respiratory Medicine,China-Japan Friendship Hospital,Beijing,100029,China [7]National Center for Respiratory Medicine,Institute of Respiratory Medicine,Chinese Academy of Medical Sciences,National Clinical Research Center for Respiratory Diseases,Beijing,100029,China [8]Department of Basic Medical Sciences,School of Medicine,Tsinghua University,Beijing,100084,China [9]Key Laboratory of Cellular Physiology at Shanxi Medical University,Ministry of Education,Shanxi Medical University,Taiyuan,030012,China

出　　处：《Acta Pharmacologica Sinica》2022年第4期908-918,共11页中国药理学报（英文版）

基　　金：This work was financially supported by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences[grant number:2018-12M-1-001](to CW);the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences[grant number:2018RC31001](to CW);the National Natural Science Foundation of China(91739107)(to JW).

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-α, IL-1β, 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.

关 键 词：SILICOSIS pirfenidone INTERLEUKIN-17A inflammation FIBROSIS 

分 类 号：R56[医药卫生—呼吸系统] R965[医药卫生—内科学]