Abstract
Transforming growth factor (TGF)-alpha is a ligand for the epidermal growth factor receptor (EGFR). EGFR activation is associated with fibroproliferative processes in human lung disease and animal models of pulmonary fibrosis. Overexpression of TGF-alpha in transgenic mice causes progressive and severe pulmonary fibrosis; however, the intracellular signaling pathways downstream of EGFR mediating this response are unknown. Using a doxycycline-regulatable transgenic mouse model of lung-specific TGF-alpha expression, we observed increased PCNA protein and phosphorylation of Akt and p70S6K in whole lung homogenates in association with induction of TGF-alpha. Induction in the lung of TGF-alpha caused progressive pulmonary fibrosis over a 7-week period. Daily administration of rapamycin prevented accumulation of total lung collagen, weight loss, and changes in pulmonary mechanics. Treatment of mice with rapamycin 4 weeks after the induction of TGF-alpha prevented additional weight loss, increases in total collagen, and changes in pulmonary mechanics. Rapamycin prevented further increases in established pulmonary fibrosis induced by EGFR activation. This study demonstrates that mammalian target of rapamycin (mTOR) is a major effector of EGFR-induced pulmonary fibrosis, providing support for further studies to determine the role of mTOR in the pathogenesis and treatment of pulmonary fibrosis.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Carrier Proteins / antagonists & inhibitors*
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Carrier Proteins / metabolism
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Collagen / metabolism
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Disease Models, Animal
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Disease Progression
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Doxycycline / pharmacology
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Enzyme Inhibitors / pharmacology*
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ErbB Receptors / antagonists & inhibitors
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ErbB Receptors / metabolism
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Erlotinib Hydrochloride
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Gene Expression Regulation
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Humans
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Lung / drug effects*
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Lung / enzymology
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Lung / physiopathology
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Mice
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Mice, Transgenic
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation
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Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors*
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Phosphotransferases (Alcohol Group Acceptor) / metabolism
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Proliferating Cell Nuclear Antigen / metabolism
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins c-akt / metabolism
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Pulmonary Fibrosis / genetics
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Pulmonary Fibrosis / metabolism
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Pulmonary Fibrosis / physiopathology
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Pulmonary Fibrosis / prevention & control*
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Quinazolines / pharmacology
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Respiratory Mechanics / drug effects
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Ribosomal Protein S6 Kinases, 70-kDa / metabolism
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Signal Transduction / drug effects*
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Sirolimus / pharmacology*
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TOR Serine-Threonine Kinases
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Time Factors
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Transforming Growth Factor alpha / genetics
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Transforming Growth Factor alpha / metabolism*
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Uteroglobin / genetics
Substances
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Carrier Proteins
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Enzyme Inhibitors
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Proliferating Cell Nuclear Antigen
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Protein Kinase Inhibitors
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Quinazolines
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SCGB1A1 protein, human
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Scgb1a1 protein, mouse
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Transforming Growth Factor alpha
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Collagen
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Uteroglobin
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Erlotinib Hydrochloride
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Phosphotransferases (Alcohol Group Acceptor)
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MTOR protein, human
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mTOR protein, mouse
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EGFR protein, mouse
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ErbB Receptors
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Proto-Oncogene Proteins c-akt
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Ribosomal Protein S6 Kinases, 70-kDa
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TOR Serine-Threonine Kinases
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Doxycycline
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Sirolimus