title: Increased FGF1-FGFRc expression in idiopathic pulmonary fibrosis.
abstract: BACKGROUND
  Recent clinical studies show that tyrosine kinase inhibitors slow the rate of lung function decline and decrease the number of acute exacerbations in patients with Idiopathic Pulmonary Fibrosis (IPF). However, in the murine bleomycin model of fibrosis, not all tyrosine kinase signaling is detrimental. Exogenous ligands Fibroblast Growth Factor (FGF) 7 and 10 improve murine lung repair and increase survival after injury via tyrosine kinase FGF receptor 2b-signaling. Therefore, the level and location of FGF/FGFR expression as well as the exogenous effect of the most highly expressed FGFR2b ligand, FGF1, was analyzed on human lung fibroblasts.
  
  
  METHODS
  FGF ligand and receptor expression was evaluated in donor and IPF whole lung homogenates using western blotting and qPCR. Immunohistochemistry for FGF1 and FGFR1/2/3/4 were performed on human lung tissue. Lastly, the effects of FGF1, a potent, multi-FGFR ligand, were studied on primary cultures of IPF and non-IPF donor fibroblasts. Western blots for pro-fibrotic markers, proliferation, FACS for apoptosis, transwell assays and MetaMorph analyses on cell cultures were performed.
  
  
  RESULTS
  Whole lung homogenate analyses revealed decreased FGFR b-isoform expression, and an increase in FGFR c-isoform expression. Of the FGFR2b-ligands, FGF1 was the most significantly increased in IPF patients; downstream targets of FGF-signaling, p-ERK1/2 and p-AKT were also increased. Immunohistochemistry revealed FGF1 co-localization within basal cell sheets, myofibroblast foci, and Surfactant protein-C positive alveolar epithelial type-II cells as well as co-localization with FGFR1, FGFR2, FGFR3, FGFR4 and myofibroblasts expressing the migratory marker Fascin. Both alone and in the presence of heparin, FGF1 led to increased MAPK-signaling in primary lung fibroblasts. While smooth muscle actin was unchanged, heparin + FGF1 decreased collagen production in IPF fibroblasts. In addition, FGF1 + heparin increased apoptosis and cell migration. The FGFR inhibitor (PD173074) attenuated these effects.
  
  
  CONCLUSIONS
  Strong expression of FGF1/FGFRs in pathogenic regions of IPF suggest that aberrant FGF1-FGFR signaling is increased in IPF patients and may contribute to the pathogenesis of lung fibrosis by supporting fibroblast migration and increased MAPK-signaling.
authors.affiliation: German Center for Lung Research, Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Giessen, Hessen, Germany.
authors.forename: BreAnne
authors.initials: B
authors.lastname: MacKenzie
authors.affiliation: German Center for Lung Research, Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Giessen, Hessen, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Korfei
authors.affiliation: German Center for Lung Research, Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Giessen, Hessen, Germany.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Henneke
authors.affiliation: German Center for Lung Research, Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Giessen, Hessen, Germany.
authors.forename: Zaneta
authors.initials: Z
authors.lastname: Sibinska
authors.affiliation: German Center for Lung Research, Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Giessen, Hessen, Germany.
authors.forename: Xia
authors.initials: X
authors.lastname: Tian
authors.affiliation: German Center for Lung Research, Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Giessen, Hessen, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Hezel
authors.affiliation: German Center for Lung Research, Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Giessen, Hessen, Germany.
authors.forename: Salma
authors.initials: S
authors.lastname: Dilai
authors.affiliation: German Center for Lung Research, Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Giessen, Hessen, Germany.
authors.forename: Roxana
authors.initials: R
authors.lastname: Wasnick
authors.affiliation: German Center for Lung Research, Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Giessen, Hessen, Germany.
authors.forename: Beate
authors.initials: B
authors.lastname: Schneider
authors.affiliation: German Center for Lung Research, Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Giessen, Hessen, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Wilhelm
authors.affiliation: German Center for Lung Research, Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Giessen, Hessen, Germany.
authors.forename: Elie
authors.initials: E
authors.lastname: El Agha
authors.affiliation: Department of Thoracic Surgery, General Hospital University Vienna, Vienna, Austria.
authors.forename: Walter
authors.initials: W
authors.lastname: Klepetko
authors.affiliation: German Center for Lung Research, Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Giessen, Hessen, Germany.|German Center for Lung Research, Greifenstein, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.affiliation: German Center for Lung Research, Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Giessen, Hessen, Germany.|German Center for Lung Research, Greifenstein, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Schermuly
authors.affiliation: German Center for Lung Research, Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Giessen, Hessen, Germany.|German Center for Lung Research, Greifenstein, Germany.|AGAPLESION Lung Clinic Waldhof-Elgershausen, Greifenstein, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Günther
authors.affiliation: German Center for Lung Research, Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Giessen, Hessen, Germany. Saverio.Bellusci@innere.med.uni-giessen.de.|German Center for Lung Research, Greifenstein, Germany. Saverio.Bellusci@innere.med.uni-giessen.de.|Developmental Biology Program, Division of Surgery, Saban Research Institute of Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA, USA. Saverio.Bellusci@innere.med.uni-giessen.de.|Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 18 Kremlyovskaya Street, Kazan, 420008, Russian Federation. Saverio.Bellusci@innere.med.uni-giessen.de.
authors.forename: Saverio
authors.initials: S
authors.lastname: Bellusci
mesh_terms: D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D016220:Fibroblast Growth Factor 1 / Q000096:biosynthesis*; D005786:Gene Expression Regulation; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000378:metabolism* / Q000473:pathology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D017468:Receptors, Fibroblast Growth Factor / Q000096:biosynthesis*
chemical_list: D017468:Receptors, Fibroblast Growth Factor; D016220:Fibroblast Growth Factor 1