title: Rapamycin decreases airway remodeling and hyperreactivity in a transgenic model of noninflammatory lung disease.
abstract: 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-α (TGF-α) transgenic mice null for the transcription factor early growth response-1 (Egr-1) (TGF-α 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-α Tg/Egr-1(ko/ko) mice lost body weight and developed severe AHR after 3 wk of lung-specific TGF-α 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-α induction. Increases in tissue damping and airway elastance were also attenuated in transgenic mice treated with rapamycin. TGF-α/Egr-1(ko/ko) mice on doxycycline for 8 wk developed severe airway remodeling. Immunostaining for α-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-α expression for 8 wk. Thus rapamycin reduced airway remodeling and AHR, demonstrating an important role for mTOR signaling in TGF-α-induced/EGF receptor-mediated reactive airway disease.
authors: Section of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.
authors: Elizabeth L
authors: EL
authors: Kramer
authors: William D
authors: WD
authors: Hardie
authors: Elizabeth M
authors: EM
authors: Mushaben
authors: Thomas H
authors: TH
authors: Acciani
authors: Patricia A
authors: PA
authors: Pastura
authors: Thomas R
authors: TR
authors: Korfhagen
authors: Gurjit Khurana
authors: GK
authors: Hershey
authors: Jeffrey A
authors: JA
authors: Whitsett
authors: Timothy D
authors: TD
authors: Le Cras
mesh_terms: D056151:Airway Remodeling / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D051766:Early Growth Response Protein 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D066246:ErbB Receptors / Q000502:physiology; D008171:Lung Diseases / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000502:physiology; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000502:physiology
chemical_list: D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D012333:RNA, Messenger; D016211:Transforming Growth Factor alpha; C546843:mTOR protein, mouse; D066246:ErbB Receptors; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus