Imatinib ameliorates bronchiolitis obliterans via inhibition of fibrocyte migration and differentiation

Satoshi Watanabe*, Kazuo Kasahara, Yuko Waseda, Hazuki Takato, Shingo Nishikawa, Taro Yoneda, Johsuke Hara, Takashi Sone, Miki Abo, Hideharu Kimura, Shinji Nakao

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)138-147
Number of pages10
JournalJournal of Heart and Lung Transplantation
Volume36
Issue number2
DOIs
StatePublished - Feb 1 2017

Keywords

  • PDGF
  • bronchiolitis obliterans
  • c-Abl
  • fibrocyte
  • imatinib
  • tyrosine kinase inhibitor

ASJC Scopus subject areas

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine
  • Transplantation

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