Received for publication September 11, 2006.
Revised January 9, 2007.
Accepted for publication January 10, 2007.

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 anti-fibrotic therapeutic agent. In this study, the efficacy of imatinib mesylate to modulate fibrogenic responses, both in-vitro and in-vivo, were 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. Additionally, imatinib inhibits lung epithelial cell proliferation and survival, but not the induction of epithelial-mesenchymal transition. Imatinib does not alter transforming growth factor-/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 intra-peritoneal injection or oral gavage), administered during the post-injury 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 anti-fibrotic effects in late stages of tissue injury-repair. Pharmacologic agents that modulate the activities and fate of differentiated (myo)fibroblasts, while not interfering with the regenerative capacity of epithelial cells, are likely to be more effective for treatment of nonresolving, progressive fibrotic disorders.

Key words: Cell differentiation, Cell proliferation, Cell survival, Fibroblast, Pulmonary fibrosis, Transforming growth factor-beta

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