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Updated: Sep 6, 2025
Oropharyngeal Administration of Bleomycin in the Murine Model of Pulmonary Fibrosis
Published on: May 9, 2025
Bone morphogenetic protein 4 inhibits pulmonary fibrosis by modulating cellular senescence and mitophagy in lung
Ruijuan Guan1,2,3, Liang Yuan1,3, Jingpei Li1,2,3
1State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Background:
Accumulation of myofibroblasts is critical to fibrogenesis in idiopathic pulmonary fibrosis (IPF). Senescence and insufficient mitophagy in fibroblasts contribute to their differentiation into myofibroblasts, thereby promoting the development of lung fibrosis. Bone morphogenetic protein 4 (BMP4), a multifunctional growth factor, is essential for the early stage of lung development; however, the role of BMP4 in modulating lung fibrosis remains unknown.
Methods:
The aim of this study was to evaluate the role of BMP4 in lung fibrosis using BMP4-haplodeleted mice, BMP4-overexpressed mice, primary lung fibroblasts and lung samples from patients with IPF.
Results:
BMP4 expression was downregulated in IPF lungs and fibroblasts compared to control individuals, negatively correlated with fibrotic genes, and BMP4 decreased with transforming growth factor (TGF)-β1 stimulation in lung fibroblasts in a time- and dose-dependent manner. In mice challenged with bleomycin, BMP4 haploinsufficiency perpetuated activation of lung myofibroblasts and caused accelerated lung function decline, severe fibrosis and mortality. BMP4 overexpression using adeno-associated virus 9 vectors showed preventative and therapeutic efficacy against lung fibrosis. In vitro, BMP4 attenuated TGF-β1-induced fibroblast-to-myofibroblast differentiation and extracellular matrix (ECM) production by reducing impaired mitophagy and cellular senescence in lung fibroblasts. Pink1 silencing by short-hairpin RNA transfection abolished the ability of BMP4 to reverse the TGF-β1-induced myofibroblast differentiation and ECM production, indicating dependence on Pink1-mediated mitophagy. Moreover, the inhibitory effect of BMP4 on fibroblast activation and differentiation was accompanied with an activation of Smad1/5/9 signalling and suppression of TGF-β1-mediated Smad2/3 signalling in vivo and in vitro.
Conclusion:
Strategies for enhancing BMP4 signalling may represent an effective treatment for pulmonary fibrosis.
Insights
Bone morphogenetic protein 4 (BMP4) deficiency exacerbates lung fibrosis by promoting myofibroblast differentiation. Enhancing BMP4 signaling may offer a novel therapeutic strategy for idiopathic pulmonary fibrosis (IPF).
Area of Science:
- Pulmonary Medicine
- Cell Biology
- Molecular Biology
Background:
- Idiopathic pulmonary fibrosis (IPF) is characterized by myofibroblast accumulation.
- Fibroblast senescence and impaired mitophagy contribute to myofibroblast differentiation in lung fibrosis.
- The role of Bone morphogenetic protein 4 (BMP4) in pulmonary fibrosis is not well understood.
Purpose of the Study:
- To investigate the role of BMP4 in the pathogenesis of lung fibrosis.
- To evaluate BMP4 as a potential therapeutic target for IPF.
Main Methods:
- Utilized BMP4-haplodeleted and BMP4-overexpressed mice models.
- Examined primary human lung fibroblasts and IPF patient lung samples.
- Assessed fibroblast differentiation, extracellular matrix production, mitophagy, and senescence.
Main Results:
- BMP4 expression was reduced in IPF lungs and fibroblasts, correlating negatively with fibrotic genes.
- BMP4 deficiency worsened bleomycin-induced lung fibrosis, while BMP4 overexpression showed therapeutic effects.
- BMP4 attenuated TGF-β1-induced fibroblast activation by enhancing Pink1-mediated mitophagy and reducing senescence, involving Smad1/5/9 and Smad2/3 signaling pathways.
Conclusions:
- BMP4 plays a protective role in lung fibrosis.
- Strategies aimed at enhancing BMP4 signaling hold promise for treating pulmonary fibrosis.
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