title: FGF9 and FGF18 in idiopathic pulmonary fibrosis promote survival and migration and inhibit myofibroblast differentiation of human lung fibroblasts in vitro.
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.
authors.affiliation: INSERM U1152, DHU FIRE, Labex Inflamex, Université Paris Diderot, Sorbonne Paris Cité.
authors.forename: Audrey
authors.initials: A
authors.lastname: Joannes
authors.affiliation: INSERM U1152, DHU FIRE, Labex Inflamex, Université Paris Diderot, Sorbonne Paris Cité.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Brayer
authors.affiliation: INSERM U1152, DHU FIRE, Labex Inflamex, Université Paris Diderot, Sorbonne Paris Cité.
authors.forename: Valérie
authors.initials: V
authors.lastname: Besnard
authors.affiliation: INSERM U1152, DHU FIRE, Labex Inflamex, Université Paris Diderot, Sorbonne Paris Cité.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Marchal-Sommé
authors.affiliation: INSERM U1152, DHU FIRE, Labex Inflamex, Université Paris Diderot, Sorbonne Paris Cité.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Jaillet
authors.affiliation: INSERM U1152, DHU FIRE, Labex Inflamex, Université Paris Diderot, Sorbonne Paris Cité, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Service de Chirurgie Thoracique et Vasculaire, and.
authors.forename: Pierre
authors.initials: P
authors.lastname: Mordant
authors.affiliation: INSERM U1152, DHU FIRE, Labex Inflamex, Université Paris Diderot, Sorbonne Paris Cité, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Service de Pneumologie et Transplantation, Paris, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Mal
authors.affiliation: INSERM U1152, DHU FIRE, Labex Inflamex, Université Paris Diderot, Sorbonne Paris Cité, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Service de Pneumologie A.
authors.forename: Raphael
authors.initials: R
authors.lastname: Borie
authors.affiliation: INSERM U1152, DHU FIRE, Labex Inflamex, Université Paris Diderot, Sorbonne Paris Cité, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Service de Pneumologie A, bruno.crestani@bch.aphp.fr.
authors.forename: Bruno
authors.initials: B
authors.lastname: Crestani
authors.affiliation: INSERM U1152, DHU FIRE, Labex Inflamex, Université Paris Diderot, Sorbonne Paris Cité.
authors.forename: Arnaud A
authors.initials: AA
authors.lastname: Mailleux
mesh_terms: D000368:Aged; D016022:Case-Control Studies; D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D051525:Fibroblast Growth Factor 9 / Q000502:physiology*; D005346:Fibroblast Growth Factors / Q000502:physiology*; D015870:Gene Expression; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D058628:Myofibroblasts / Q000502:physiology*; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism*
chemical_list: C496459:FGF9 protein, human; D051525:Fibroblast Growth Factor 9; D017468:Receptors, Fibroblast Growth Factor; C113569:fibroblast growth factor 18; D005346:Fibroblast Growth Factors
keywords: FGF18; FGF9; IPF; apoptosis; differentiation; lung fibroblasts; migration