title: Anti-fibrotic effects of nintedanib in lung fibroblasts derived from patients with idiopathic pulmonary fibrosis.
abstract: BACKGROUND
  Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis. The kinase inhibitor nintedanib specific for vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR) significantly reduced the rate of decline of forced vital capacity versus placebo.
  
  
  OBJECTIVE
  To determine the in vitro effect of nintedanib on primary human lung fibroblasts.
  
  
  METHODS
  Fibroblasts were isolated from lungs of IPF patients and from non-fibrotic controls. We assessed the effect of VEGF, PDGF-BB and basic FGF (bFGF) ± nintedanib on: (i) expression/activation of VEGFR, PDGFR, and FGFR, (ii) cell proliferation, secretion of (iii) matrix metalloproteinases (MMP), (iv) tissue inhibitor of metalloproteinase (TIMP), and (v) collagen.
  
  
  RESULTS
  IPF fibroblasts expressed higher levels of PDGFR and FGFR than controls. PDGF-BB, bFGF, and VEGF caused a pro-proliferative effect which was prevented by nintedanib. Nintedanib enhanced the expression of pro-MMP-2, and inhibited the expression of TIMP-2. Transforming growth factor-beta-induced secretion of collagens was inhibited by nintedanib.
  
  
  CONCLUSIONS
  Our data demonstrate a significant anti-fibrotic effect of nintedanib in IPF fibroblasts. This effect consists of the drug's anti-proliferative capacity, and on its effect on the extracellular matrix, the degradation of which seems to be enhanced.
authors.affiliation: Pulmonary Cell Research, Department of Biomedicine, University Hospital Basel, Basel, 4031, Switzerland. katrin.hostettler@usb.ch.|Clinics of Respiratory Medicine, University Hospital Basel, Petersgraben 4, Basel, 4031, Switzerland. katrin.hostettler@usb.ch.
authors.forename: Katrin E
authors.initials: KE
authors.lastname: Hostettler
authors.affiliation: Pulmonary Cell Research, Department of Biomedicine, University Hospital Basel, Basel, 4031, Switzerland. Jun.zhong@unibas.ch.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhong
authors.affiliation: Department of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece. epap@med.auth.gr.
authors.forename: Eleni
authors.initials: E
authors.lastname: Papakonstantinou
authors.affiliation: Department of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece. gkaraki@med.auth.gr.
authors.forename: George
authors.initials: G
authors.lastname: Karakiulakis
authors.affiliation: Pulmonary Cell Research, Department of Biomedicine, University Hospital Basel, Basel, 4031, Switzerland. michael.tamm@usb.ch.|Clinics of Respiratory Medicine, University Hospital Basel, Petersgraben 4, Basel, 4031, Switzerland. michael.tamm@usb.ch.
authors.forename: Michael
authors.initials: M
authors.lastname: Tamm
authors.affiliation: Pulmonary Cell Research, Department of Biomedicine, University Hospital Basel, Basel, 4031, Switzerland. petra.seidel@unibas.ch.
authors.forename: Petra
authors.initials: P
authors.lastname: Seidel
authors.affiliation: Pulmonary Cell Research, Department of Biomedicine, University Hospital Basel, Basel, 4031, Switzerland. qingzhu.sun@unibas.ch.
authors.forename: Qingzhu
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Pulmonary Cell Research, Department of Biomedicine, University Hospital Basel, Basel, 4031, Switzerland. jyotshna.mandal@usb.ch.
authors.forename: Jyotshna
authors.initials: J
authors.lastname: Mandal
authors.affiliation: Clinics of Thoracic Surgery, University Hospital Basel, Basel, 4031, Switzerland. didier.lardinois@usb.ch.
authors.forename: Didier
authors.initials: D
authors.lastname: Lardinois
authors.affiliation: Department of Internal Medicine IV, University of Vienna, Vienna, 1090, Austria. clambers@gmx.de.
authors.forename: Christopher
authors.initials: C
authors.lastname: Lambers
authors.affiliation: Pulmonary Cell Research, Department of Biomedicine, University Hospital Basel, Basel, 4031, Switzerland. Michael.roth@usb.ch.
authors.forename: Michael
authors.initials: M
authors.lastname: Roth
mesh_terms: D000077214:Becaplermin; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004792:Enzyme Precursors / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D018093:Gelatinases / Q000378:metabolism; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000201:enzymology* / Q000473:pathology; D007211:Indoles / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology; D017468:Receptors, Fibroblast Growth Factor / Q000187:drug effects / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000187:drug effects / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000187:drug effects / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
chemical_list: D004792:Enzyme Precursors; D007211:Indoles; D047428:Protein Kinase Inhibitors; D020574:Proto-Oncogene Proteins c-sis; D017468:Receptors, Fibroblast Growth Factor; C560823:TIMP2 protein, human; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D019716:Tissue Inhibitor of Metalloproteinase-2; D000077214:Becaplermin; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor; D018093:Gelatinases; C069860:progelatinase; C530716:nintedanib