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Combined therapy with pirfenidone and nintedanib counteracts fibrotic silicosis in mice
  • +8
  • Lu Bai,
  • Jiaxin Wang,
  • Xue Wang,
  • Jixin Wang,
  • Wei Zeng,
  • Junling Pang,
  • Tiantian Zhang,
  • Shengxi Li,
  • Meiyue Song,
  • Jing Wang,
  • Chen Wang
Lu Bai
State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College
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Jiaxin Wang
Peking-Tsinghua Joint Center for Life Sciences
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Xue Wang
Harbin Medical University
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Jixin Wang
Tsinghua University School of Medicine
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Wei Zeng
State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College
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Junling Pang
State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College
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Tiantian Zhang
State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College
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Shengxi Li
State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College
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Meiyue Song
State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College
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Jing Wang
State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College

Corresponding Author:[email protected]

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Chen Wang
State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College
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Abstract

Abstract Background and Purpose Pneumoconiosis, especially silicosis has emerged as a prominent occupational disease with remarkable global implications with no definitive cure available. While pirfenidone and nintedanib have been approved in treating idiopathic pulmonary fibrosis, their potential efficacy as anti-fibrotic agents in advanced silicosis warrants further investigation. Thus, we aimed to assess the individual and combined effects of pirfenidone and nintedanib in treating advanced silicosis mice and further elucidate the underlying mechanisms involved in their therapeutic actions. Experimental Approach We administrated monotherapy or combination therapy of pirfenidone and nintedanib with low and high doses in silicosis mouse models established after 6 weeks and then evaluated lung function, inflammatory responses, and fibrotic status. Moreover, we employed transcriptomic and metabolomic analyses to unravel the mechanisms underlying different therapeutic strategies. Key Results Both pirfenidone and nintedanib were demonstrated to be effective for advanced silicosis, with superior outcomes when used in combination. Transcriptomic and metabolomic analyses revealed that pirfenidone and nintedanib primarily exerted their therapeutic effects through modulation of immune responses, signaling cascades, circadian rhythm, and metabolic processes of substances including lipid, amino acids, nucleotides, and carbohydrates. Conclusion and Implications In conclusion, pirfenidone and nintedanib, either administered individually or in combination, exhibit remarkable potential in advanced silicosis mouse models. Further, combined therapy outperformed monotherapy even at a half dose. These therapeutic benefits are attributed to their influence on diverse signaling pathways and metabolic processes. Keywords: silicosis, pulmonary fibrosis, pirfenidone, nintedanib, multi-omics.
17 Oct 2023Submitted to British Journal of Pharmacology
20 Oct 2023Submission Checks Completed
20 Oct 2023Assigned to Editor
20 Oct 2023Review(s) Completed, Editorial Evaluation Pending
26 Oct 2023Reviewer(s) Assigned
19 May 2024Reviewer(s) Assigned
10 Jul 2024Editorial Decision: Revise Minor
19 Sep 20242nd Revision Received
20 Sep 2024Review(s) Completed, Editorial Evaluation Pending
20 Sep 2024Submission Checks Completed
20 Sep 2024Assigned to Editor
09 Oct 2024Editorial Decision: Accept