FGF9 and FGF18 in idiopathic pulmonary fibrosis promote survival and migration and inhibit myofibroblast differentiation of human lung fibroblasts in vitro

Am J Physiol Lung Cell Mol Physiol. 2016 Apr 1;310(7):L615-29. doi: 10.1152/ajplung.00185.2015. Epub 2016 Jan 15.

Abstract

Idiopathic pulmonary fibrosis (IPF) is characterized by an accumulation of extracellular matrix proteins and fibroblasts in the distal airways. Key developmental lung signaling pathways are reactivated in IPF. For instance, fibroblast growth factor 9 (FGF9) and FGF18, involved in epithelial-mesenchymal interactions, are critical for lung development. We evaluated the expression of FGF9, FGF18, and FGF receptors (FGFRs) in lung tissue from controls and IPF patients and assessed their effect on proliferation, survival, migration, and differentiation of control and IPF human lung fibroblasts (HLFs). FGF9, FGF18, and all FGFRs were present in the remodeled alveolar epithelium close to the fibroblast foci in IPF lungs. FGFR3 was generally detected in fibroblast foci by immunohistochemistry. In vitro, HLFs mainly expressed mesenchyme-associated FGFR isoforms (FGFR1c and FGFR3c) and FGFR4. FGF9 did not affect fibroblast proliferation, whereas FGF18 inhibited cell growth in control fibroblasts. FGF9 and FGF18 decreased Fas-ligand-induced apoptosis in control but not in IPF fibroblasts. FGF9 prevented transforming growth factor β1-induced myofibroblast differentiation. FGF9 and FGF18 increased the migratory capacities of HLF, and FGF9 actively modulated matrix metalloproteinase activity. In addition, FGFR3 inhibition by small interfering RNA impacted p-ERK activation by FGF9 and FGF18 and their effects on differentiation and migration. These results identify FGF9 as an antiapoptotic and promigratory growth factor on HLF, maintaining fibroblasts in an undifferentiated state. The biological effects of FGF9 and FGF18 were partially driven by FGFR3. FGF18 was a less potent molecule. Both growth factors likely contribute to the fibrotic process in vivo.

Keywords: FGF18; FGF9; IPF; apoptosis; differentiation; lung fibroblasts; migration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Case-Control Studies
  • Cell Differentiation
  • Cell Proliferation
  • Cell Survival
  • Cells, Cultured
  • Fibroblast Growth Factor 9 / physiology*
  • Fibroblast Growth Factors / physiology*
  • Gene Expression
  • Humans
  • Idiopathic Pulmonary Fibrosis
  • Lung / metabolism
  • Lung / pathology
  • Middle Aged
  • Myofibroblasts / physiology*
  • Receptors, Fibroblast Growth Factor / metabolism*

Substances

  • FGF9 protein, human
  • Fibroblast Growth Factor 9
  • Receptors, Fibroblast Growth Factor
  • fibroblast growth factor 18
  • Fibroblast Growth Factors