Rapamycin decreases airway remodeling and hyperreactivity in a transgenic model of noninflammatory lung disease

Kramer EL, Hardie WD, Mushaben EM, Acciani TH, Pastura PA, Korfhagen TR, Hershey GK, Whitsett JA, Le Cras TD. Rapamycin decreases airway remodeling and hyperreactivity in a transgenic model of noninflammatory lung disease. J Appl Physiol 111: 1760-1767, 2011. First published September 8, 2011; doi:10.1152/japplphysiol.00737.2011.-Airway hyperreactivity (AHR) and remodeling are cardinal features of asthma and chronic obstructive pulmonary disease. New therapeutic targets are needed as some patients are refractory to current therapies and develop progressive airway remodeling and worsening AHR. The mammalian target of rapamycin (mTOR) is a key regulator of cellular proliferation and survival. Treatment with the mTOR inhibitor rapamycin inhibits inflammation and AHR in allergic asthma models, but it is unclear if rapamycin can directly inhibit airway remodeling and AHR, or whether its therapeutic effects are entirely mediated through immunosuppression. To address this question, we utilized transforming growth factor-alpha (TGF-alpha) transgenic mice null for the transcription factor early growth response-1 (Egr-1) (TGF-alpha Tg/Egr-1(ko/ko) mice). These mice develop airway smooth muscle thickening and AHR in the absence of altered lung inflammation, as previously reported. In this study, TGF-alpha Tg/Egr-1(ko/ko) mice lost body weight and developed severe AHR after 3 wk of lung-specific TGF-alpha induction. Rapamycin treatment prevented body weight loss, airway wall thickening, abnormal lung mechanics, and increases in airway resistance to methacholine after 3 wk of TGF-alpha induction. Increases in tissue damping and airway elastance were also attenuated in transgenic mice treated with rapamycin. TGF-alpha/Egr-1(ko/ko) mice on doxycycline for 8 wk developed severe airway remodeling. Immunostaining for alpha-smooth muscle actin and morphometric analysis showed that rapamycin treatment prevented airway smooth muscle thickening around small airways. Pentachrome staining, assessments of lung collagen and fibronectin mRNA levels, indicated that rapamycin also attenuated fibrotic pathways induced by TGF-alpha expression for 8 wk. Thus rapamycin reduced airway remodeling and AHR, demonstrating an important role for mTOR signaling in TGF-alpha-induced/EGF receptor-mediated reactive airway disease.