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.
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Acknowledgements
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) and the National Natural Science Foundation of China (91739107) (to JW).
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ZJC designed the project, performed experiments, analyzed data and drafted the manuscript. YL designed the project, performed experiments and analyzed data. ZZ, ZGL, MYS, XMQ, BCL, and XRZ contributed to the construction of silicosis models and helped collect experimental samples. JLP and ZFH performed bioinformatic analysis. PRY, HPD, JW, and CW helped design the project, commented on the manuscript and supervised all aspects of the project.
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Cao, Zj., Liu, Y., Zhang, Z. et al. Pirfenidone ameliorates silica-induced lung inflammation and fibrosis in mice by inhibiting the secretion of interleukin-17A. Acta Pharmacol Sin 43, 908–918 (2022). https://doi.org/10.1038/s41401-021-00706-4
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DOI: https://doi.org/10.1038/s41401-021-00706-4
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