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Updated: Feb 26, 2026
Oropharyngeal Administration of Bleomycin in the Murine Model of Pulmonary Fibrosis
Published on: May 9, 2025
A FGFR3 decoy receptor attenuates lung fibroblast-to-myofibroblast transition and pulmonary fibrosis
Célia Scribe1,2, Diogo Gonçalves1, Marine Gautier-Isola2
1Rare Disease, Worldwide Research and Development, Pfizer, Nice, France.
Abstract:
Fibroblast growth factor (FGF) signaling plays an important role in the pathogenesis of various respiratory diseases, including idiopathic pulmonary fibrosis (IPF). FGF ligands can exert both pro and anti-fibrotic effects, depending on the responding cell, the expression levels of FGF receptors (FGFR1-4), and the context of other signaling molecules such as Transforming growth factor β (TGF-β). We evaluated here the effect of a modified version of a soluble FGFR3 decoy receptor (designated as "sFGFR3-Fc"), which specifically sequesters profibrotic FGFR3 ligands, FGF1, FGF2, and FGF9 as a potential anti-fibrotic drug. We showed that FGF2 stimulated proliferation and expression of various fibrotic markers in human pulmonary fibroblasts from healthy donors and IPF patients. The sFGFR3-Fc was able to reduce these FGF2-mediated responses and also partially attenuate the profibrotic phenotype induced by TGF-β, including gel contraction. Furthermore, single-cell transcriptomic analyses revealed heterogeneity of IPF-derived fibroblasts for FGF2 response and confirmed the potential efficacy of sFGFR3-Fc in decreasing the expression of a subset of TGF-β1 pathway genes. Finally, sFGFR3-Fc was shown to improve the progression of pulmonary fibrosis using both a preventive and therapeutic strategy, evaluated in the standard single bleomycin (BLM) instillation mouse model as well as in a more severe model of repeated BLM instillations, as evidenced by the reduction in ECM deposits, the recovery of body weight, and the restoration of lung function. Our data highlight the interplay between the TGF-β and the FGF signaling pathways and demonstrates the potential of targeting profibrotic FGFR3 ligands as a therapeutic strategy for IPF.
Insights
A novel soluble FGFR3 decoy receptor (sFGFR3-Fc) effectively reduced fibroblast proliferation and fibrotic markers in idiopathic pulmonary fibrosis (IPF) models. This targeted approach shows promise for treating fibrotic lung diseases by modulating fibroblast growth factor (FGF) signaling.
Area of Science:
- Pulmonary Medicine
- Fibrosis Research
- Molecular Biology
Background:
- Fibroblast growth factor (FGF) signaling is implicated in idiopathic pulmonary fibrosis (IPF) pathogenesis.
- FGF ligands can have dual pro- and anti-fibrotic effects, influenced by FGF receptors (FGFRs) and other signaling pathways like Transforming Growth Factor-beta (TGF-β).
Purpose of the Study:
- To evaluate the anti-fibrotic potential of a soluble FGFR3 decoy receptor (sFGFR3-Fc) that sequesters pro-fibrotic FGFR3 ligands (FGF1, FGF2, FGF9).
- To investigate the interplay between TGF-β and FGF signaling in IPF and assess sFGFR3-Fc efficacy in preclinical models.
Main Methods:
- Assessed FGF2-induced fibroblast proliferation and fibrotic marker expression in human pulmonary fibroblasts (healthy and IPF).
- Evaluated sFGFR3-Fc's ability to attenuate FGF2 and TGF-β-induced pro-fibrotic responses.
- Utilized single-cell transcriptomic analysis to explore fibroblast heterogeneity and TGF-β pathway gene expression.
- Tested sFGFR3-Fc in bleomycin (BLM)-induced pulmonary fibrosis mouse models (single and repeated instillation).
Main Results:
- FGF2 stimulated proliferation and fibrotic markers in human pulmonary fibroblasts.
- sFGFR3-Fc reduced FGF2-mediated responses and partially attenuated TGF-β-induced pro-fibrotic phenotypes.
- Single-cell analysis revealed FGF2 response heterogeneity and confirmed sFGFR3-Fc's efficacy in downregulating a subset of TGF-β1 pathway genes.
- sFGFR3-Fc improved pulmonary fibrosis progression, reduced extracellular matrix (ECM) deposits, and restored lung function in mouse models.
Conclusions:
- Targeting pro-fibrotic FGFR3 ligands with sFGFR3-Fc is a potential therapeutic strategy for IPF.
- The study highlights the significant interaction between TGF-β and FGF signaling pathways in fibrotic lung disease.
- sFGFR3-Fc demonstrates therapeutic potential for IPF by modulating key fibrotic signaling pathways.
Related Concept Videos
01:16TGF - β Signaling Pathway
01:09Introduction to Fibroblasts