title: Nintedanib inhibits fibroblast activation and ameliorates fibrosis in preclinical models of systemic sclerosis.
abstract: BACKGROUND
  Nintedanib is a tyrosine kinase inhibitor that has recently been shown to slow disease progression in idiopathic pulmonary fibrosis in two replicate phase III clinical trials. The aim of this study was to analyse the antifibrotic effects of nintedanib in preclinical models of systemic sclerosis (SSc) and to provide a scientific background for clinical trials in SSc.
  
  
  METHODS
  The effects of nintedanib on migration, proliferation, myofibroblast differentiation and release of extracellular matrix of dermal fibroblasts were analysed by microtitre tetrazolium and scratch assays, stress fibre staining, qPCR and SirCol assays. The antifibrotic effects of nintedanib were evaluated in bleomycin-induced skin fibrosis, in a murine sclerodermatous chronic graft-versus-host disease model and in tight-skin-1 mice.
  
  
  RESULTS
  Nintedanib dose-dependently reduced platelet-derived growth factor-induced and transforming growth factor-β-induced proliferation and migration as well as myofibroblast differentiation and collagen release of dermal fibroblasts from patients with and healthy individuals. Nintedanib also inhibited the endogenous activation of SSc fibroblasts. Nintedanib prevented bleomycin-induced skin fibrosis in a dose-dependent manner and was also effective in the treatment of established fibrosis. Moreover, treatment with nintedanib ameliorated fibrosis in the chronic graft-versus-host disease model and in tight-skin-1 mice in well-tolerated doses.
  
  
  CONCLUSIONS
  We demonstrate that nintedanib effectively inhibits the endogenous as well as cytokine-induced activation of SSc fibroblasts and exerts potent antifibrotic effects in different complementary mouse models of SSc. These data have direct translational implications for clinical trials with nintedanib in SSc.
authors: Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors: Jingang
authors: J
authors: Huang
authors: Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors: Christian
authors: C
authors: Beyer
authors: Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors: Katrin
authors: K
authors: Palumbo-Zerr
authors: Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors: Yun
authors: Y
authors: Zhang
authors: Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors: Andreas
authors: A
authors: Ramming
authors: Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors: Alfiya
authors: A
authors: Distler
authors: Department of Trauma Surgery, University of Erlangen-Nuremberg, Erlangen, Germany.
authors: Kolja
authors: K
authors: Gelse
authors: Center of Experimental Rheumatology, Research of Systemic Autoimmune Diseases, University Hospital Zurich, Zurich, Switzerland.
authors: Oliver
authors: O
authors: Distler
authors: Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors: Georg
authors: G
authors: Schett
authors: Boehringer-Ingelheim Pharma, Div. Research Germany, Biberach, Germany.
authors: Lutz
authors: L
authors: Wollin
authors: Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors: Jörg H W
authors: JH
authors: Distler
mesh_terms: D000818:Animals; D001761:Bleomycin; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D005347:Fibroblasts / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D005355:Fibrosis; D006086:Graft vs Host Disease / Q000517:prevention & control; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D012595:Scleroderma, Systemic / Q000188:drug therapy* / Q000473:pathology; D012867:Skin / Q000187:drug effects / Q000473:pathology
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; D001761:Bleomycin; C530716:nintedanib
keywords: Fibroblasts; Systemic Sclerosis; Treatment