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Published ahead of print on February 25, 2005, doi:10.1164/rccm.200404-531OC
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American Journal of Respiratory and Critical Care Medicine Vol 171. pp. 1279-1285, (2005)
© 2005 American Thoracic Society
doi: 10.1164/rccm.200404-531OC

Original Article

Imatinib as a Novel Antifibrotic Agent in Bleomycin-induced Pulmonary Fibrosis in Mice

Yoshinori Aono, Yasuhiko Nishioka, Mami Inayama, Momoyo Ugai, Jun Kishi, Hisanori Uehara, Keisuke Izumi and Saburo Sone

Departments of Internal Medicine and Molecular Therapeutics, and Molecular and Environmental Pathology, Course of Medical Oncology, University of Tokushima School of Medicine, Tokushima, Japan

Correspondence and requests for reprints should be addressed to Saburo Sone, M.D., Ph.D., Department of Internal Medicine and Molecular Therapeutics, Course of Medical Oncology, University of Tokushima School of Medicine, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan. E-mail: ssone{at}clin.med.tokushima-u.ac.jp

Imatinib mesylate is a potent and specific tyrosine kinase inhibitor against c-ABL, BCR-ABL, and c-KIT, and has been demonstrated to be highly active in chronic myeloid leukemia and gastrointestinal stromal tumors. We examined the antifibrotic effects of imatinib using a bleomycin-induced lung fibrosis model in mice because imatinib also inhibits tyrosine kinase of platelet-derived growth factor receptors (PDGFRs). Imatinib inhibited the growth of primary murine lung fibroblasts and the autophosphorylation of PDGFR-ß induced by PDGF. Administration of imatinib significantly prevented bleomycin-induced pulmonary fibrosis in mice, partly by reducing the number of mesenchymal cells incorporating bromodeoxyuridine. Analysis of bronchoalveolar lavage cells demonstrated that imatinib did not suppress early inflammation on Days 7 and 14 caused by bleomycin. These results suggest that imatinib has the potential to prevent pulmonary fibrosis by inhibiting the proliferation of mesenchymal cells, and that imatinib might be useful for the treatment of pulmonary fibrosis in humans.

Key Words: fibroblast • platelet-derived growth factor • tyrosine kinase




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