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Rapamycin Prevents Transforming Growth Factor-–Induced Pulmonary Fibrosis

¹ Divisions of Pulmonary Biology and ² Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio

Correspondence and requests for reprints should be addressed to William D. Hardie, M.D., Department of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229. E-mail: william.hardie{at}cchmc.org.

Transforming growth factor (TGF)- 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- 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- expression, we observed increased PCNA protein and phosphorylation of Akt and p70S6K in whole lung homogenates in association with induction of TGF-. Induction in the lung of TGF- 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- 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.

Key Words: epidermal growth factor receptor • PI3K • Akt • mTOR

CLINICAL RELEVANCE Expression of epidermal growth factor receptor (EGFR) and EGFR ligands have been identified in animal models of pulmonary fibrosis and human disease. Using a transgenic mouse model of pulmonary fibrosis caused by lung-specific expression of the EGFR ligand, transforming growth factor-, the present study demonstrates that administration of rapamycin prevents both the initiation and the progression of established pulmonary fibrosis and associated alterations in lung mechanics. These findings support the need for further studies to carefully determine the role of mammalian target of rapamycin activation in the pathogenesis of pulmonary fibrosis and to assess the efficacy of therapies designed to inhibit its activity.