FGF21 Signaling Exerts Antifibrotic Properties during Pulmonary Fibrosis

Abstract Rationale Idiopathic pulmonary fibrosis (IPF) is a lethal disease with limited therapeutic options. FGF21 (fibroblast growth factor 21), an endocrine fibroblast growth factor that acts through the FGFR1 (fibroblast growth factor receptor 1)/KLB (β-Klotho) pathway, mitigates liver fibrosis. Objectives We hypothesized that FGF21 could exert antifibrotic properties in the lung. Methods The concentrations of FGF21 and KLB in the plasma of patients with IPF and control subjects were assessed. Pulmonary fibrosis development was assessed in Fgf21-deficient mice compared with wild-type littermates, at Day 14 (D14) after the intratracheal injection of bleomycin. We determined the effect of repeated subcutaneous injections of a PEGylated FGF21 analog at D7, D10, D14, and D17 after bleomycin on the development of pulmonary fibrosis. Mice were killed at D21. The effects of FGF21, alone or with KLB, on apoptosis in murine lung epithelial 15 cells and on the phenotype of human lung fibroblasts were assessed in vitro. Measurements and Main Results In the plasma of patients with IPF, FGF21 concentrations were increased, while KLB concentrations were decreased. Fgf21-deficient mice showed increased sensitivity to bleomycin in comparison with their wild-type littermates. Treatment with PEGylated FGF21 mitigated lung fibrogenesis, as evidenced by a lower injury score and decreased fibrosis markers and profibrotic mediator expression compared with the control group receiving the diluent. In murine lung epithelial 15 cells, stimulation with FGF21 and KLB inhibited apoptosis, through the decrease of BAX and BIM. Fibroblastic phenotype remained unaltered. Conclusions Our data indicate a possible antifibrotic effect of FGF21 in the lung achieved through the inhibition of alveolar type 2 cell apoptosis.