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 Show more
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"), that specifically sequesters pro-fibrotic 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 pro-fibrotic 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 demonstrate the potential of targeting pro-fibrotic FGFR3 ligands as therapeutic strategy for IPF. Show less