Effects of the protein kinase inhibitor, imatinib mesylate, on epithelial/mesenchymal phenotypes

Implications for treatment of fibrotic diseases

Ragini Vittal, Hengmin Zhang, MeiLan K. Han, Bethany B. Moore, Jeffrey C. Horowitz, Victor J. Thannickal

Research output: Contribution to journalArticle

49 Citations (Scopus)

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-β/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.

Original languageEnglish (US)
Pages (from-to)35-44
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume321
Issue number1
DOIs
StatePublished - Apr 2007
Externally publishedYes

Fingerprint

Protein Kinase Inhibitors
Phenotype
Myofibroblasts
Fibrosis
Fibroblasts
Lung Injury
Lung
Therapeutics
Epithelial Cells
Re-Epithelialization
Platelet-Derived Growth Factor Receptors
Epithelial-Mesenchymal Transition
Bleomycin
Wounds and Injuries
Transforming Growth Factors
Imatinib Mesylate
Mammals
Cell Survival
Collagen
Epithelium

ASJC Scopus subject areas

  • Pharmacology

Cite this

Effects of the protein kinase inhibitor, imatinib mesylate, on epithelial/mesenchymal phenotypes : Implications for treatment of fibrotic diseases. / Vittal, Ragini; Zhang, Hengmin; Han, MeiLan K.; Moore, Bethany B.; Horowitz, Jeffrey C.; Thannickal, Victor J.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 321, No. 1, 04.2007, p. 35-44.

Research output: Contribution to journalArticle

Vittal, Ragini ; Zhang, Hengmin ; Han, MeiLan K. ; Moore, Bethany B. ; Horowitz, Jeffrey C. ; Thannickal, Victor J. / Effects of the protein kinase inhibitor, imatinib mesylate, on epithelial/mesenchymal phenotypes : Implications for treatment of fibrotic diseases. In: Journal of Pharmacology and Experimental Therapeutics. 2007 ; Vol. 321, No. 1. pp. 35-44.
@article{6275dbea29864dc1bfd53e679ce0b619,
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-β/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.",
author = "Ragini Vittal and Hengmin Zhang and Han, {MeiLan K.} and Moore, {Bethany B.} and Horowitz, {Jeffrey C.} and Thannickal, {Victor J.}",
year = "2007",
month = "4",
doi = "10.1124/jpet.106.113407",
language = "English (US)",
volume = "321",
pages = "35--44",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "1",

}

TY - JOUR

T1 - Effects of the protein kinase inhibitor, imatinib mesylate, on epithelial/mesenchymal phenotypes

T2 - Implications for treatment of fibrotic diseases

AU - Vittal, Ragini

AU - Zhang, Hengmin

AU - Han, MeiLan K.

AU - Moore, Bethany B.

AU - Horowitz, Jeffrey C.

AU - Thannickal, Victor J.

PY - 2007/4

Y1 - 2007/4

N2 - 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-β/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.

AB - 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-β/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.

UR - http://www.scopus.com/inward/record.url?scp=33947411686&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33947411686&partnerID=8YFLogxK

U2 - 10.1124/jpet.106.113407

DO - 10.1124/jpet.106.113407

M3 - Article

VL - 321

SP - 35

EP - 44

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 1

ER -