title: EGF receptor tyrosine kinase inhibitors diminish transforming growth factor-alpha-induced pulmonary fibrosis.
abstract: Transforming growth factor-alpha (TGF-alpha) 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-alpha-induced pulmonary fibrosis. Using a doxycycline-regulatable transgenic mouse model of lung-specific TGF-alpha 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-alpha 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-alpha 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.
authors.affiliation: Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229, USA. william.hardie@cchmc.org
authors.forename: William D
authors.initials: WD
authors.lastname: Hardie
authors.forename: Cynthia
authors.initials: C
authors.lastname: Davidson
authors.forename: Machiko
authors.initials: M
authors.lastname: Ikegami
authors.forename: George D
authors.initials: GD
authors.lastname: Leikauf
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Le Cras
authors.forename: Adrienne
authors.initials: A
authors.lastname: Prestridge
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Whitsett
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Korfhagen
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D004318:Doxycycline / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D051379:Mice; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control; D011799:Quinazolines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D016211:Transforming Growth Factor alpha
chemical_list: D011799:Quinazolines; D012333:RNA, Messenger; D016211:Transforming Growth Factor alpha; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D004318:Doxycycline; D000077156:Gefitinib