title: Imatinib ameliorates bronchiolitis obliterans via inhibition of fibrocyte migration and differentiation.
abstract: BACKGROUND
  Imatinib, a tyrosine kinase inhibitor, has been proposed as a potential anti-fibrotic agent for fibroproliferative diseases, including bronchiolitis obliterans (BO). However, the underlying anti-fibrotic mechanisms of the agent remain unclear. We evaluated whether bone (BM)-derived progenitor cells, fibrocytes, might be a target of imatinib in the attenuation of BO.
  
  
  METHODS
  We used a murine BO model induced by heterotopic tracheal transplantation and assessed the origin of fibroblasts by using green fluorescent protein-BM chimeric mice. We also evaluated the effects of imatinib on luminal obstruction and fibrocyte accumulation. The effects of imatinib on fibrocyte migration and differentiation were assessed by culturing fibrocytes in vitro.
  
  
  RESULTS
  In the murine BO model, tracheal allografts showed epithelial injury and developed complete luminal occlusion 28 days after transplantation. Most of the mesenchymal cells that had accumulated in the tracheal allograft were derived from BM cells. Imatinib treatment ameliorated the airway luminal occlusion and significantly reduced the number of fibrocytes in the allografts. In vitro studies showed that imatinib inhibited migration of cultured blood fibrocytes via the platelet-derived growth factor/platelet-derived growth factor receptor axis. Imatinib also inhibited differentiation of fibrocytes via suppression of c-Abl activity that was essential for the differentiation of monocytes to fibrocytes.
  
  
  CONCLUSIONS
  Imatinib prevents airway luminal obstruction by inhibiting the migration and differentiation of fibrocytes. Fibrocytes may be a novel target in the prevention and treatment of BO.
authors.affiliation: Departments of (a)Respiratory Medicine,. Electronic address: swatanabe@staff.kanazawa-u.ac.jp.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: Departments of (a)Respiratory Medicine.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kasahara
authors.affiliation: Departments of (a)Respiratory Medicine.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Waseda
authors.affiliation: Departments of (a)Respiratory Medicine.
authors.forename: Hazuki
authors.initials: H
authors.lastname: Takato
authors.affiliation: Departments of (a)Respiratory Medicine.
authors.forename: Shingo
authors.initials: S
authors.lastname: Nishikawa
authors.affiliation: Departments of (a)Respiratory Medicine.
authors.forename: Taro
authors.initials: T
authors.lastname: Yoneda
authors.affiliation: Departments of (a)Respiratory Medicine.
authors.forename: Johsuke
authors.initials: J
authors.lastname: Hara
authors.affiliation: Departments of (a)Respiratory Medicine.
authors.forename: Takashi
authors.initials: T
authors.lastname: Sone
authors.affiliation: Departments of (a)Respiratory Medicine.
authors.forename: Miki
authors.initials: M
authors.lastname: Abo
authors.affiliation: Departments of (a)Respiratory Medicine.
authors.forename: Hideharu
authors.initials: H
authors.lastname: Kimura
authors.affiliation: Hematology, Cellular Transplantation Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Nakao
mesh_terms: D000818:Animals; D001707:Biopsy, Needle; D001989:Bronchiolitis Obliterans / Q000188:drug therapy* / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011897:Random Allocation; D012680:Sensitivity and Specificity; D018709:Statistics, Nonparametric
chemical_list: D000068877:Imatinib Mesylate
keywords: PDGF; bronchiolitis obliterans; c-Abl; fibrocyte; imatinib; tyrosine kinase inhibitor