Identification of FGFR4 as a regulator of myofibroblast differentiation in Pulmonary Fibrosis.

Introduction IPF is a devastating lung disease with limited therapeutic options. FGFR4 is a known receptor for several paracrine Fibroblast growth factors (FGFs). FGFR4 is also the main receptor for FGF19, an endocrine FGF that was demonstrated by our group to have anti-fibrotic properties in the lung. We aimed to determine whether FGFR4 could modulate pulmonary fibrogenesis. Methods We assessed FGFR4 mRNA and protein levels in IPF and control lungs. In vitro, we determined the effect of TGF-b, Endothelin-1 and PDGF on FGFR4 expression in human lung fibroblasts. We determined the effect FGFR4 inhibition, using a specific pharmacological inhibitor (FGF401), or genetic deletion in murine embryonic fibroblasts (MEFs) on TGF-b-induced myofibroblastic differentiation. In vivo, we evaluated the development of bleomycin-induced lung fibrosis in Fgfr4-deficient (Fgfr4-/-) mice compared to Wild Type littermates (WT), and after FGF401 treatment in WT mice compared to a control group receiving the solvent only. Results FGFR4 was decreased in IPF lungs as compared to control lungs, at mRNA and protein levels. In vitro, FGFR4 was downregulated after treatment by TGF- ß, Endothelin-1 and PDGF. In vitro, FGFR4 inhibition by FGF401 prevented TGF-b1-induced collagen and ACTA2 increase in lung fibroblasts. Similar results were observed in Fgfr4-/- MEFs. In vivo, FGFR4 genetic deficiency or FGFR4 pharmacological inhibition did not modulate bleomycin-induced pulmonary fibrosis. Conclusion Our data suggest that FGFR4 exerts pro-fibrotic properties by enhancing TGF- ß signaling in vitro. However, the inhibition of FGFR4 is not sufficient to prevent the development of pulmonary fibrosis in vivo.

FGF19 Is Downregulated in Idiopathic Pulmonary Fibrosis and Inhibits Lung Fibrosis in Mice.

Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with limited therapeutic possibilities. FGF19 (fibroblast growth factor 19), an endocrine FGF, was recently shown to decrease liver fibrosis. To ask whether FGF19 had antifibrotic properties in the lung and decipher its effects on common features associated with lung fibrogenesis, we assessed, by ELISA, FGF19 concentrations in plasma and BAL fluids obtained from control subjects and patients with IPF. In vivo, using an intravenously administered adeno11-associated virus, we overexpressed FGF19 at the fibrotic phase of two experimental models of murine lung fibrosis and assessed its effect on lung morphology, lung collagen content, fibrosis markers, and profibrotic mediator expression at mRNA and protein levels. In vitro, we investigated whether FGF19 could modulate the TGF-ß-induced differentiation of primary human lung fibroblasts into myofibroblasts and the apoptosis of murine alveolar type II cells. Although FGF19 was not detected in BAL fluid, FGF19 concentration was decreased in the plasma of patients with IPF compared with control subjects. In vivo, the overexpression of FGF19 was associated with a marked decrease of lung fibrosis and fibrosis markers, with a decrease of profibrotic mediator expression and lung collagen content. In vitro, FGF19 decreased alveolar type 2 epithelial cell apoptosis through the decrease of the proapoptotic BIM protein expression and prevented TGF-ß-induced myofibroblast differentiation through the inhibition of JNK phosphorylation. Altogether, these data identify FGF19 as an antifibrotic molecule with potential therapeutic interest in fibrotic lung disorders.

Thoracic Air-Leak Syndrome Complicating Allogeneic Hematopoietic Stem-Cell Transplantation.

We report a case of thoracic air-leak syndrome, an extremely rare complication developed after an episode of organizing pneumonia due to graft-vs-host disease in a 19-year-old male. This unusual non-infectious pulmonary complication occurred 527 days after allogeneic HSCT and led to the patient's death within 1 month due to cardio-respiratory failure. Herein, we highlight chest-imaging aspects which are typical. Early detection by high-resolution chest CT could improve patient management.