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Published ahead of print on February 25, 2005, doi:10.1164/rccm.200404-531OC

Am. J. Respir. Crit. Care Med., Volume 171, Number 11, June 2005, 1279-1285

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Submitted on April 26, 2004
Accepted on February 16, 2005

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

Yoshinori Aono1, Yasuhiko Nishioka1, Mami Inayama1, Momoyo Ugai1, Jun Kishi1, Hisanori Uehara1, Keisuke Izumi1, and Saburo Sone1*

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

* To whom correspondence should be addressed. 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 stromall tumors. Here we examined the anti-fibrotic effects of imatinib using a bleomycin-induced lung fibrosis model in mice because imatinib also inhibits tyrosine kinase of platelet-derived growth factor receptors (PDGFR). Imatinib inhibited the growth of primary murine lung fibroblasts and the autophosphorylation of PDGFR-{beta} induced by PDGF. Administration of imatinib significantly prevented bleomycin-induced pulmonary fibrosis. Analysis of bronchoalveolar lavage cells demonstrated that imatinib did not suppress early inflammation on days 7 and 14 caused by bleomycin, but clearly ameliorated subsequent fibrosis in the late stages. These results suggest that PDGF could be a critical growth factor in the pathogenesis of bleomycin-induced pulmonary fibrosis, and that imatinib might be useful for the treatment of pulmonary fibrosis in humans.
Key words: platelet-derived growth factor, tyrosine kinase, fibroblast




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