title: Treatment with imatinib prevents fibrosis in different preclinical models of systemic sclerosis and induces regression of established fibrosis.
abstract: OBJECTIVE
  Imatinib is a small-molecule tyrosine kinase inhibitor capable of selective, dual inhibition of the transforming growth factor beta and platelet-derived growth factor (PDGF) pathways. Imatinib has previously been shown to prevent the development of inflammation-driven experimental fibrosis when treatment was initiated before administration of the profibrotic stimulus. The aim of this study was to confirm the efficacy of imatinib in a murine model of systemic sclerosis (SSc) that is less driven by inflammation and to investigate whether imatinib is also effective for the treatment of established fibrosis.
  
  
  METHODS
  The tight skin 1 (TSK-1) mouse model of SSc was used to evaluate the antifibrotic effects of imatinib in a genetic model of the later stages of SSc. In addition, the efficacy of imatinib for the treatment of preestablished fibrosis was analyzed in a modified model of bleomycin-induced dermal fibrosis in which the application of bleomycin was prolonged and the onset of treatment was late.
  
  
  RESULTS
  Treatment with imatinib reduced dermal and hypodermal thickening in TSK-1 mice and prevented the differentiation of resting fibroblasts into myofibroblasts. In the model of preestablished dermal fibrosis, imatinib not only stopped further progression of fibrosis but also induced regression of preexisting dermal fibrosis, with a reduction in dermal thickness below pretreatment levels.
  
  
  CONCLUSIONS
  These results indicate that combined inhibition of the tyrosine kinase c-Abl and PDGF receptor might be effective in the later, less inflammatory stages of SSc and for the treatment of established fibrosis. Thus, imatinib might be an interesting candidate for clinical trials in patients with longstanding disease and preexisting tissue fibrosis.
authors.affiliation: Department of Internal Medicine III, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Alfiya
authors.initials: A
authors.lastname: Akhmetshina
authors.forename: Paulius
authors.initials: P
authors.lastname: Venalis
authors.forename: Clara
authors.initials: C
authors.lastname: Dees
authors.forename: Nicole
authors.initials: N
authors.lastname: Busch
authors.forename: Jochen
authors.initials: J
authors.lastname: Zwerina
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.forename: Oliver
authors.initials: O
authors.lastname: Distler
authors.forename: Jörg H W
authors.initials: JH
authors.lastname: Distler
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic; D001549:Benzamides; D001761:Bleomycin; D004195:Disease Models, Animal; D000071837:Fibrillins; D005355:Fibrosis; D000068877:Imatinib Mesylate; D051379:Mice; D008811:Mice, Inbred DBA; D008817:Mice, Mutant Strains; D008840:Microfilament Proteins / Q000235:genetics; D010641:Phenotype; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D012867:Skin / Q000473:pathology; D012871:Skin Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology*
chemical_list: D000903:Antibiotics, Antineoplastic; D001549:Benzamides; D000071837:Fibrillins; D008840:Microfilament Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D001761:Bleomycin; D000068877:Imatinib Mesylate; D017479:Receptors, Platelet-Derived Growth Factor; D016315:Proto-Oncogene Proteins c-abl