title: Angiotensin receptor blockade attenuates cigarette smoke-induced lung injury and rescues lung architecture in mice.
abstract: Chronic obstructive pulmonary disease (COPD) is a prevalent smoking-related disease for which no disease-altering therapies currently exist. As dysregulated TGF-β signaling associates with lung pathology in patients with COPD and in animal models of lung injury induced by chronic exposure to cigarette smoke (CS), we postulated that inhibiting TGF-β signaling would protect against CS-induced lung injury. We first confirmed that TGF-β signaling was induced in the lungs of mice chronically exposed to CS as well as in COPD patient samples. Importantly, key pathological features of smoking-associated lung disease in patients, e.g., alveolar injury with overt emphysema and airway epithelial hyperplasia with fibrosis, accompanied CS-induced alveolar cell apoptosis caused by enhanced TGF-β signaling in CS-exposed mice. Systemic administration of a TGF-β-specific neutralizing antibody normalized TGF-β signaling and alveolar cell death, conferring improved lung architecture and lung mechanics in CS-exposed mice. Use of losartan, an angiotensin receptor type 1 blocker used widely in the clinic and known to antagonize TGF-β signaling, also improved oxidative stress, inflammation, metalloprotease activation and elastin remodeling. These data support our hypothesis that inhibition of TGF-β signaling through angiotensin receptor blockade can attenuate CS-induced lung injury in an established murine model. More importantly, our findings provide a preclinical platform for the development of other TGF-β-targeted therapies for patients with COPD.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Podowski
authors.forename: Carla
authors.initials: C
authors.lastname: Calvi
authors.forename: Shana
authors.initials: S
authors.lastname: Metzger
authors.forename: Kaori
authors.initials: K
authors.lastname: Misono
authors.forename: Hataya
authors.initials: H
authors.lastname: Poonyagariyagorn
authors.forename: Armando
authors.initials: A
authors.lastname: Lopez-Mercado
authors.forename: Therese
authors.initials: T
authors.lastname: Ku
authors.forename: Thomas
authors.initials: T
authors.lastname: Lauer
authors.forename: Sharon
authors.initials: S
authors.lastname: McGrath-Morrow
authors.forename: Alan
authors.initials: A
authors.lastname: Berger
authors.forename: Christopher
authors.initials: C
authors.lastname: Cheadle
authors.forename: Rubin
authors.initials: R
authors.lastname: Tuder
authors.forename: Harry C
authors.initials: HC
authors.lastname: Dietz
authors.forename: Wayne
authors.initials: W
authors.lastname: Mitzner
authors.forename: Robert
authors.initials: R
authors.lastname: Wise
authors.forename: Enid
authors.initials: E
authors.lastname: Neptune
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D019808:Losartan / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008806:Mice, Inbred AKR; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D015656:Respiratory Mechanics / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D012907:Smoking / Q000009:adverse effects*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D044140:Receptor, Angiotensin, Type 1; D016212:Transforming Growth Factor beta; D019808:Losartan