title: Effects of the protein kinase inhibitor, imatinib mesylate, on epithelial/mesenchymal phenotypes: implications for treatment of fibrotic diseases.
abstract: Tissue injury in mammals triggers both inflammatory and repair responses that, in some contexts, results in fibrosis. Fibrosis is characterized by the persistence of activated myofibroblasts, ineffective re-epithelialization, and variable degrees of inflammation within injured tissues. The protein kinase inhibitor (PKI), imatinib mesylate, has been proposed as a potential antifibrotic therapeutic agent. In this study, the efficacy of imatinib mesylate to modulate fibrogenic responses, both in vitro and in vivo, was examined. In an in vitro fibroblast culture model, imatinib inhibits platelet-derived growth factor receptor activation and fibroblast proliferation but not the stably differentiated myofibroblast phenotype. Furthermore, imatinib inhibits lung epithelial cell proliferation and survival but not the induction of epithelial-mesenchymal transition. Imatinib does not alter transforming growth factor-beta/SMAD3 signaling in either cell type. In a murine model of lung fibrosis, bleomycin-induced injury to the pulmonary epithelium provokes an early inflammatory response with more delayed fibrosis during the late reparative phase of lung injury. Imatinib mesylate (10 mg/kg/day by i.p. injection or oral gavage), administered during the postinjury repair phase, failed to significantly alter fibrogenic responses assessed by histopathology, collagen content, and the accumulation of myofibroblasts within the injured lung. These studies indicate that the capacity of a PKI to inhibit fibroblast proliferation may be insufficient to mediate significant antifibrotic effects in late stages of tissue injury repair. Pharmacologic agents that modulate the activities and fate of differentiated (myo)fibroblasts, without interfering with the regenerative capacity of epithelial cells, are likely to be more effective for treatment of nonresolving, progressive fibrotic disorders.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical Center, 6301 MSRB III, 1150 W. Medical Center Drive, Ann Arbor, MI 48109, USA.
authors.forename: Ragini
authors.initials: R
authors.lastname: Vittal
authors.forename: Hengmin
authors.initials: H
authors.lastname: Zhang
authors.forename: Meilan K
authors.initials: MK
authors.lastname: Han
authors.forename: Bethany B
authors.initials: BB
authors.lastname: Moore
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Horowitz
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Thannickal
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000964:Antimetabolites, Antineoplastic; D001549:Benzamides; D001761:Bleomycin; D015153:Blotting, Western; D001973:Bromodeoxyuridine; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004277:DNA, Single-Stranded / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects*; D005347:Fibroblasts / Q000187:drug effects; D005355:Fibrosis / Q000188:drug therapy*; D046152:Gastrointestinal Stromal Tumors / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D007150:Immunohistochemistry; D007202:Indicators and Reagents; D007274:Injections, Intraperitoneal; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology; D008171:Lung Diseases / Q000139:chemically induced / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000187:drug effects*; D051379:Mice; D010641:Phenotype; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000964:Antimetabolites, Antineoplastic; D001549:Benzamides; D004277:DNA, Single-Stranded; D007202:Indicators and Reagents; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D001761:Bleomycin; D000068877:Imatinib Mesylate; D003094:Collagen; D053148:Caspase 3; D001973:Bromodeoxyuridine