Imatinib mesylate inhibits the profibrogenic activity of TGF-beta and prevents bleomycin-mediated lung fibrosis.
Idiopathic pulmonary fibrosis is a progressive and fatal fibrotic disease of the lungs with unclear etiology. Prior efforts to treat idiopathic pulmonary fibrosis that focused on anti-inflammatory therapy have not proven to be effective. Recent insight suggests that the pathogenesis is mediated through foci of dysregulated fibroblasts driven by profibrotic cytokine signaling. TGF-beta and PDGF are 2 of the most potent of these cytokines. In the current study, we investigated the role of TGF-beta-induced fibrosis mediated by activation of the Abelson (Abl) tyrosine kinase. Our data indicate that fibroblasts respond to TGF-beta by stimulating c-Abl kinase activity independently of Smad2/3 phosphorylation or PDGFR activation. Moreover, inhibition of c-Abl by imatinib prevented TGF-beta-induced ECM gene expression, morphologic transformation, and cell proliferation independently of any effect on Smad signaling. Further, using a mouse model of bleomycin-induced pulmonary fibrosis, we found a significant inhibition of lung fibrosis by imatinib. Thus, Abl family members represent common targets for the modulation of profibrotic cytokine signaling.
Daniels
Craig E
CE
Thoracic Disease Research Unit, Division of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
Wilkes
Mark C
MC
Edens
Maryanne
M
Kottom
Ted J
TJ
Murphy
Stephen J
SJ
Limper
Andrew H
AH
Leof
Edward B
EB
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D001761:Bleomycin / Q000009:adverse effects* / Q000494:pharmacology; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D000068877:Imatinib Mesylate; D047468:Immunoprecipitation; D007249:Inflammation; D008156:Luciferases / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D010879:Piperazines / Q000494:pharmacology*; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053781:Transforming Growth Factor beta2; D019076:Transgenes
D000970:Antineoplastic Agents; D001549:Benzamides; D016207:Cytokines; D005353:Fibronectins; D010879:Piperazines; D011743:Pyrimidines; D016212:Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2; D001761:Bleomycin; D000068877:Imatinib Mesylate; D003094:Collagen; D008156:Luciferases; D017479:Receptors, Platelet-Derived Growth Factor; D016315:Proto-Oncogene Proteins c-abl