Involvement of FGF21 in pulmonary fibrosis

Abstract

<b>Introduction:</b> Fibroblast Growth Factors (FGF) are reactivated during Idiopathic Pulmonary Fibrosis (IPF). FGF21, an endocrine FGF that acts through the FGFR1/ beta-klotho (KLB) pathway was shown to prevent liver fibrosis in mice. We asked whether FGF21 was involved in the lung fibrotic process. <b>Methods:</b> We assessed FGF21 and KLB plasma concentration in 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 and tunicamycin on a murine 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. <b>Results:</b> 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 KLB was decreased (1968.3 vs 2853.8 pg/ml, p=0.001). FGFR1 was expressed similarly in total lungs of IPF and control patients at mRNA level, whereas KLB was decreased in IPF lungs. FGF21 was not expressed. In vitro, FGF21 ± KLB did not influence fibroblast proliferation and migration, and did not modify TGF- ß-induced fibroblast to myofibroblast differentiation. FGF21 associated with KLB decreased MLE15 cells apoptosis, with a decrease in cleaved-PARP expression by western blot, but did not prevent HLF apoptosis. <b>Conclusion:</b> Plasma FGF21 concentration is increased in IPF patients. In vitro, FGF21 inhibited apoptosis of MLE15 cells in vitro when associated to KLB. These data indicate a possible antifibrotic effect of FGF21 in the lung.