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: Satoshi Watanabe, Kazuo Kasahara, Yuko Waseda, Hazuki Takato, Shingo Nishikawa, Taro Yoneda, Johsuke Hara, Takashi Sone, Miki Abo, Hideharu Kimura, Shinji Nakao
• Journal: The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation (J Heart Lung Transplant) Vol. 36 Issue 2 Pg. 138-147 (Feb 2017) ISSN: 1557-3117 [Electronic] United States
• PMID: 27388852 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Chemical References

• Imatinib Mesylate

Topics

• Animals
• Biopsy, Needle
• Bronchiolitis Obliterans (drug therapy, pathology)
• Cell Differentiation (drug effects)
• Cell Movement (drug effects)
• Cells, Cultured
• Disease Models, Animal
• Fibroblasts (cytology, drug effects)
• Imatinib Mesylate (pharmacology)
• Immunohistochemistry
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Random Allocation
• Sensitivity and Specificity
• Statistics, Nonparametric