Implication of FGFR4 and its ligands in Idiopathic Pulmonary Fibrosis

IPF is characterized by a reactivation of signaling pathways involved in lung development, such as Fibroblast Growth Factors (FGF). FGFR4 is a FGF receptor activated by endocrine FGFs, such as FGF19, in the presence of the co-receptor s klotho. Recent evidence indicates that complete deletion of FGFR4 and Fgf15 (murine orthologue of FGF19) leads to increased liver fibrosis suggesting that the FGFR4/FGF19 axis has some antifibrotic properties. The aim of this work was to study the regulation of FGFR4 expression and to assess the effect of its activation/inibition on the lung fibroblast phenotype. Material and Methods: We assessed FGFR4, s klotho and FGF19 expression by immunohistochemistry RT-PCR in lung tissue from controls and IPF patients. Human lung fibroblasts from IPF and control patients were stimulated in vitro with pro- or anti-fibrotic factors with or without FGF19 (20 ng/mL) during 48 hours. We studied the expression of FGFR4 at mRNA level and assessed the effect of FGF19 on fibroblast differentiation, proliferation and migration. Results: FGFR4 and s klotho were expressed by alveolar epithelial cells and by lung fibroblast in IPF lung, while FGF19 was not detected. FGFR4 mRNA expression by control and IPF fibroblasts was downregulated by pro fibrotic factors (TGFβ, CTGF, ET-1) and up-regulated by HGF. FGF9 prevented the TGFs- induced myofibroblast differentiation by significantly decreasing αSMA, Collagen1 , fibronectin, PAI-1 and CTGF at mRNA and protein levels. FGF19 increased fibroblast migration but didn9t influence proliferation. Conclusion: FGF19 inhibits TGFβ-induced differentiation in vitro. FGF19 may have anti-fibrotic properties in the lung which need to be documented in vivo.