EGF receptor tyrosine kinase inhibitors diminish transforming growth factor-α-induced pulmonary fibrosis

William D. Hardie, Cynthia Davidson, Machiko Ikegami, George D. Leikauf, Timothy D. Le Cras, Adrienne L Prestridge Savant, Jeffrey A. Whitsett, Thomas R. Korfhagen

Research output: Contribution to journalArticle

62 Scopus citations

Abstract

Transforming growth factor-α (TGF-α) is a ligand for the EGF receptor (EGFR). EGFR activation is associated with fibroproliferative processes in human lung disease and animal models of pulmonary fibrosis. We determined the effects of EGFR tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva) on the development and progression of TGF-α-induced pulmonary fibrosis. Using a doxycycline-regulatable transgenic mouse model of lung-specific TGF-α expression, we determined effects of treatment with gefitinib and erlotinib on changes in lung histology, total lung collagen, pulmonary mechanics, pulmonary hypertension, and expression of genes associated with synthesis of ECM and vascular remodeling. Induction in the lung of TGF-α caused progressive pulmonary fibrosis over an 8-wk period. Daily administration of gefitinib or erlotinib prevented development of fibrosis, reduced accumulation of total lung collagen, prevented weight loss, and prevented changes in pulmonary mechanics. Treatment of mice with gefitinib 4 wk after the induction of TGF-α prevented further increases in and partially reversed total collagen levels and changes in pulmonary mechanics and pulmonary hypertension. Increases in expression of genes associated with synthesis of ECM as well as decreases of genes associated with vascular remodeling were also prevented or partially reversed. Administration of gefitinib or erlotinib did not cause interstitial fibrosis or increases in lavage cell counts. Administration of small molecule EGFR tyrosine kinase inhibitors prevented further increases in and partially reversed pulmonary fibrosis induced directly by EGFR activation without inducing inflammatory cell influx or additional lung injury.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume294
Issue number6
DOIs
StatePublished - Jun 1 2008

Keywords

  • Erlotinib
  • Gefitinib
  • Pulmonary hypertension

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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    Hardie, W. D., Davidson, C., Ikegami, M., Leikauf, G. D., Le Cras, T. D., Prestridge Savant, A. L., Whitsett, J. A., & Korfhagen, T. R. (2008). EGF receptor tyrosine kinase inhibitors diminish transforming growth factor-α-induced pulmonary fibrosis. American Journal of Physiology - Lung Cellular and Molecular Physiology, 294(6). https://doi.org/10.1152/ajplung.00020.2008