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Updated: Oct 15, 2025
Induction of Mouse Lung Injury by Endotracheal Injection of Bleomycin
Published on: April 30, 2019
Clevudine attenuates bleomycin-induced early pulmonary fibrosis via regulating M2 macrophage polarization
Shuangling Li1, Shaoyan Gao2, Qiuyan Jiang2
1State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300000, China; High-throughput Molecular Drug Screening Centre, Tianjin International Joint Academy of Biomedicine, Tianjin 300070, China.
Abstract:
Pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease. It is a growing clinical problem which can result in breathlessness or respiratory failure and has an average life expectancy of 3 years from diagnosis. Predominantly accumulation of M2 macrophages accelerates fibrosis progression by secreting multiple cytokines that promote fibroblast to myofibroblast transition and aberrant wound healing of epithelial cells. Targeting activated macrophages to inhibit the pro-fibrotic phenotype is considered as an approach for the potential treatment of PF. Clevudine is s a purine nucleoside analogue which in an oral formulation is approved for treatment of patients with hepatitis B virus (HBV). Here, we found that clevudine is capable of suppressing pro-fibrotic phenotype (i.e., CD206, Arg1 and YM1) of M2 macrophages while enhancing anti-fibrotic phenotype (i.e., CD86, IL-6 and IL-10) by inhibiting PI3K/Akt signaling pathway. This effect further alleviates M2-induced myofibroblast activation and epithelial-to-mesenchymal transition (EMT), thus resulting in a decline of collagen deposition, pro-fibrotic cytokines secretion, with a concomitant recover ofpulmonary functions in vivo. Less infiltration of M2 macrophages between α-SMA + cells was also found in clevudine treated mice. Our findings indicate a potential anti-fibrotic effect of clevudine by regulating macrophage polarization and might be meaningful in clinical settings.
Insights
Clevudine suppresses pro-fibrotic M2 macrophages in pulmonary fibrosis (PF) by modulating their phenotype. This drug may offer a novel therapeutic strategy for PF by improving lung function.
Area of Science:
- Pulmonary medicine
- Immunology
- Pharmacology
Background:
- Pulmonary fibrosis (PF) is a progressive lung disease with poor prognosis.
- M2 macrophages accelerate PF by promoting fibroblast activation and aberrant wound healing.
- Targeting pro-fibrotic macrophages is a potential therapeutic strategy for PF.
Purpose of the Study:
- To investigate the anti-fibrotic effects of clevudine.
- To determine clevudine's mechanism of action on macrophage polarization.
- To evaluate clevudine's efficacy in a preclinical model of PF.
Main Methods:
- Assessed clevudine's impact on M2 macrophage markers (CD206, Arg1, YM1) and M1 markers (CD86, IL-6, IL-10).
- Investigated clevudine's effect on the PI3K/Akt signaling pathway.
- Evaluated clevudine's efficacy in reducing myofibroblast activation, epithelial-to-mesenchymal transition (EMT), collagen deposition, and improving lung function in vivo.
Main Results:
- Clevudine suppressed pro-fibrotic M2 macrophage markers while enhancing anti-fibrotic markers via PI3K/Akt inhibition.
- Clevudine alleviated M2-induced myofibroblast activation and EMT, reducing collagen deposition.
- Clevudine treatment improved pulmonary function and decreased M2 macrophage infiltration in vivo.
Conclusions:
- Clevudine demonstrates potential anti-fibrotic effects by regulating macrophage polarization.
- Clevudine's mechanism involves inhibiting pro-fibrotic M2 macrophage phenotypes.
- Clevudine may represent a promising therapeutic agent for pulmonary fibrosis in clinical settings.
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