FGF21 Signaling Exerts Anti-Fibrotic Properties During Pulmonary Fibrosis.

Abstract

Rationale: Idiopathic Pulmonary Fibrosis (IPF) is a lethal disease with limited therapeutic options. FGF21, an endocrine fibroblast growth factor that acts through the FGFR1/KLB pathway, mitigates liver fibrosis.

Objectives: We hypothesized that FGF21 could exert anti-fibrotic properties in the lung.

Methods: The concentrations of FGF21 and KLB in the plasma of IPF patients and control subjects were assessed. Pulmonary fibrosis development was assessed in Fgf21-deficient mice as compared to Wild Type littermates, at Day 14 after intra-tracheal injection of bleomycin. We determined the effect of repeated subcutaneous injections of a PEGylated FGF21 analog (PEG-FGF21) at D7, 10, 14 and 17 after bleomycin on the development of pulmonary fibrosis. Mice were sacrificed at D21. The effects of FGF21, alone or with KLB, on apoptosis in MLE15 cells and on the phenotype of human lung fibroblasts were assessed in vitro.

Results: In the plasma of IPF patients, FGF21 concentration was increased, while KLB levels were decreased. Fgf21 deficient mice presented an increased sensitivity to bleomycin, in comparison to their Wild Type littermate. Treatment with PEGylated FGF21 mitigated lung fibrogenesis, as evidenced by a lower injury score, decreased fibrosis markers and pro-fibrotic mediators expression as compared to the control group receiving the diluent. In MLE15 cells, stimulation with FGF21 and KLB inhibited apoptosis, through the decrease of BAX and BIM. Fibroblastic phenotype remained unaltered.

Conclusion: Our data indicate a possible anti-fibrotic effect of FGF21 in the lung achieved through the inhibition of alveolar type 2 cells apoptosis.