Imatinib mesylate inhibits fibrogenesis in asbestos-induced interstitial pneumonia.
Profibrogeneic cytokines contribute to the accumulation of myofibroblasts in the lung interstitium in idiopathic pulmonary fibrosis (IPF). Imatinib mesylate, a tyrosine kinase inhibitor specific for Abl, platelet-derived growth factor receptor (PDGFR) and c-Kit tyrosine kinases, has been shown to inhibit fibrosis and profibrotic signaling in mouse models of inflammation-mediated lung reactions. The authors tested imatinib mesylate in vivo in a mouse model of crocidolite asbestos-induced progressive fibrosis. The ability of imatinib mesylate to inhibit profibrogeneic cytokine-induced human pulmonary fibroblast migration was tested in vitro and the expression of its target protein tyrosine kinases was assessed with immunofluorescence. In vivo, 10 mg/kg/day imatinib mesylate inhibited histological parenchymal fibrosis and led to a decrease in collagen deposition, but had no significant effect on asbestos-induced neutrophilia. However, 50 mg/kg/day imatinib mesylate did not inhibit collagen deposition. In vitro, IPF fibroblasts expressed Abl, PDGFR-alpha, PDGF-beta, but not c-Kit, and 1 microM imatinib mesylate inhibited profibrogeneic cytokine-induced IPF fibroblast migration. These results suggest that imatinib mesylate is a potential and specific inhibitor of fibroblast accumulation in asbestos-induced pulmonary fibrosis.
Vuorinen
Kirsi
K
Department of Medicine and Division of Pulmonary Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
Gao
Fei
F
Oury
Tim D
TD
Kinnula
Vuokko L
VL
Myllärniemi
Marjukka
M
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D017638:Asbestos, Crocidolite / Q000633:toxicity*; D001549:Benzamides; D018929:Cell Culture Techniques; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010879:Piperazines / Q000008:administration & dosage; D011014:Pneumonia / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control*; D011743:Pyrimidines / Q000008:administration & dosage
D000970:Antineoplastic Agents; D001549:Benzamides; D036341:Intercellular Signaling Peptides and Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D017638:Asbestos, Crocidolite; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases