Involvement of FGF21 in pulmonary fibrosis

Abstract

Fibroblast Growth Factors (FGF) are reactivated during Idiopathic Pulmonary Fibrosis (IPF). FGF21, an endocrine FGF that acts through the FGFR1/KLB pathway, was shown to prevent liver fibrosis in mice. We asked whether FGF21 was involved in the lung fibrotic process. Methods : We assessed FGF21 and KLB concentrations in plasma from control (n=11) and IPF patients (n=21) by ELISA. FGF21, FGFR1 and KLB expression was measured by qPCR in total lung samples of IPF and control patients. In vitro, we assessed the effect of FGF21 ± KLB on apoptosis induced by staurosporin, tunicamycin or thapsigargin on a mouse lung type 2 alveolar epithelial cell line (MLE15 cells) and on primary Human Lung Fibroblasts (HLF) from IPF or control patients. The effect of FGF21 on TGF- ß-induced myofibroblast differentiation, proliferation and migration was assessed on primary HLF. Results : FGF21 median concentration in plasma was increased in IPF patients as compared to controls (39.9 vs 22,9 pg/ml, p=0.001) whereas the co-receptor KLB was decreased (1968.3 vs 2853.8 pg/ml, p=0.001). FGF21 and KLB concentrations in plasma were negatively correlated. KLB and FGFR1 were expressed in total lungs of IPF and control patients at mRNA level, whereas FGF21 was not. In vitro, FGF21, with or without KLB, did not modify TGF-ß-induced myofibroblast differentiation, and had no effect on proliferation and migration on HLF. FGF21, alone or associated with KLB, decreased MLE15 cells apoptosis, with a decrease in cPARP expression evaluated by western blot. Conclusion : Plasma FGF21 concentration is increased in IPF patients. In vitro, FGF21 exerts a protective effect on apoptosis on MLE15 cells in vitro. These data indicate a possible antifibrotic effect of FGF21 in the lung.