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

Abstract

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.

• Authors: 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
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 43 Issue 4 Pg. 908-918 (Apr 2022) ISSN: 1745-7254 [Electronic] United States
• PMID: 34316030 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s), under exclusive licence to CPS and SIMM.

Chemical References

• Interleukin-17
• Pyridones
• STAT Transcription Factors
• Silicon Dioxide
• pirfenidone
• Janus Kinases

Topics

• Animals
• Disease Models, Animal
• Fibrosis
• Inflammation (chemically induced, drug therapy, metabolism)
• Interleukin-17 (metabolism)
• Janus Kinases (metabolism, therapeutic use)
• Lung (metabolism)
• Mice
• Mice, Inbred C57BL
• Pneumonia (chemically induced, drug therapy, metabolism)
• Pyridones
• STAT Transcription Factors (metabolism, therapeutic use)
• Signal Transduction
• Silicon Dioxide (toxicity)