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 200mg/kg pirfenidone can effectively treat early-stage silicosis,while 400mg/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.

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

State Key Laboratory of Medical Molecular Biology,Institute of Basic Medical Sciences,Chinese Academy of Medical Sciences,Beijing 100005,China;Department of Pathophysiology,Peking Union Medical College,Beijing 100005,China;Department of Pulmonary and Critical Care Medicine,the First Hospital of Shanxi Medical University,Taiyuan 030001,China;Department of Respiratory,the Second Affiliated Hospital of Harbin Medical University,Harbin 150086,China;Beijing University of Chinese Medicine,Beijing 100029,China;Department of Pulmonary and Critical Care Medicine,Center of Respiratory Medicine,China-Japan Friendship Hospital,Beijing 100029,China;National Center for Respiratory Medicine;Institute of Respiratory Medicine,Chinese Academy of Medical Sciences;National Clinical Research Center for Respiratory Diseases,Beijing 100029,China

中国药理学报（英文版）

[1]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-.Pirfenidone ameliorates silica-induced lung inflammation and fibrosis in mice by inhibiting the secretion of interleukin-17A)[J].中国药理学报（英文版）,2022(04):908-918

Pirfenidone,Silicosis,silicosis

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