Imatinib as a novel antifibrotic agent in bleomycin-induced pulmonary fibrosis in mice.
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-beta 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.
Aono
Yoshinori
Y
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.
Nishioka
Yasuhiko
Y
Inayama
Mami
M
Ugai
Momoyo
M
Kishi
Jun
J
Uehara
Hisanori
H
Izumi
Keisuke
K
Sone
Saburo
S
D000818:Animals; D001549:Benzamides; D001761:Bleomycin; D001992:Bronchoalveolar Lavage Fluid; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000187:drug effects; D000068877:Imatinib Mesylate; D047908:Intracellular Signaling Peptides and Proteins / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D010879:Piperazines / Q000627:therapeutic use*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D011743:Pyrimidines / Q000627:therapeutic use*; D012016:Reference Values; D016896:Treatment Outcome
D001549:Benzamides; D047908:Intracellular Signaling Peptides and Proteins; D010879:Piperazines; D011743:Pyrimidines; C015482:protein kinase modulator; D001761:Bleomycin; D000068877:Imatinib Mesylate