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

Idiopathic Pulmonary Fibrosis (IPF) reuslts from dysfunctional wound repair involving fibroblasts, epithelial cells, and macrophages which respond to multiple soluble and matrix factors. Fibroblast growth factor (FGF) signaling is implicated in the pathogenesis of lung fibrosis. Individual FGF ligands may exert pro- and anti-fibrotic effects, depending on the responding cell, the expression level of the FGF receptors (FGFR1-4) and the context of other signaling molecules such as Transforming growth factor β (TGF-β). To better understand functions of FGFs on IPF, we evaluated the effect of a modified version of a FGFR3 decoy receptor, that specifically sequesters FGFR3 ligands as a potential anti-fibrotic drug. The effect of several FGFs in the presence or absence of the FGF trap was evaluated in vitro on human lung fibroblasts from healthy 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 FGF trap was also assessed in vivo on the bleomycin (BLM) mouse model by monitoring mice body weight, achcroft score, hydroxyproline and soluble collagen content. Our results revealed that FGFs (mainly FGF2) stimulate fibroblasts proliferation, contraction, ECM production and expression of various fibrotic markers. The FGF trap was able to reduce this FGF mediated pro-fibrotic phenotype. In the BLM mouse model, the FGF 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. Our data demonstrate the potential of targeting FGFR signaling as a novel therapy for IPF.