Anti-fibrotic effect of a FGF ligands trap in pulmonary fibrosis

Introduction

Lung fibrosis, including idiopathic pulmonary fibrosis (IPF), results from dysfunctional wound repair involving different cell types, including fibroblasts, epithelial cells and macrophages, which respond to multiple soluble and matrix factors. Fibroblast growth factor (FGF) signaling has been implicated in the pathogenesis of lung fibrosis, in particular in the regulation of fibroblast to myofibroblast transition (FMT), cell proliferation, and extracellular matrix production. However, individual FGF family members may exert pro- and anti-fibrotic effects, depending on the responding cell, the expression levels of the different FGF receptors (FGFR1-4) and the context of other signaling molecules, such as Transforming growth factor β (TGF-β). In order to better understand the complex functions of FGFs on pulmonary fibrosis, we evaluated the effect of a modified version of a FGFR3 decoy receptor [1] that specifically sequesters FGFR3 ligands including FGF1, FGF2 and FGF9 as a potential anti-fibrotic drug.

Methods

The effect of several FGFs in the presence or the absence of the FGFR3 ligand Trap was evaluated in vitro on human lung fibroblasts from healthy donors and IPF patients on various fibrotic parameters such as cell proliferation, cell contraction, production of extracellular matrix (ECM) and modulation of signaling pathways. The effect of the FGFR3 ligand trap was also assessed in vivo on the bleomycin mouse model, by monitoring mice body weight, Ashcroft score, hydroxyproline and soluble collagen content.

Results

Our results revealed that FGFs (mainly FGF2) stimulate fibroblast proliferation, contraction, ECM production and expression of various fibrotic markers such as chemokine ligand 2 (CCL2), connective tissue growth factor (CTGF), interleukin 6 (IL6), interleukin receptor 4 (IL4R) or ECM-related genes like fibronectin (FN1). The FGFR3 ligands Trap was able to reduce this FGF mediated pro-fibrotic phenotype and to desensitize the TGF-β canonical pathway in IPF cells. In the bleomycin lung fibrosis mouse model, the FGFR3 ligands Trap partially reversed lung fibrosis, as evidenced by a reduced body weight loss as well as diminution of the aschcroft score, hydroxyproline and soluble collagen content in lung samples.

Conclusion

Our data highlight the interplay between the TGF-β and the FGF signaling pathways in pulmonary fibrosis and demonstrate the potential of targeting FGFR3 signaling as a novel therapy for IPF.