Angiotensin receptor blockade attenuates cigarette smoke-induced lung injury and rescues lung architecture in mice

TitleAngiotensin receptor blockade attenuates cigarette smoke-induced lung injury and rescues lung architecture in mice
Publication TypeJournal Article
Year of Publication2012
AuthorsPodowski M, Calvi C, Metzger S, Misono K, Poonyagariyagorn H, Lopez-Mercado A, Ku T, Lauer T, McGrath-Morrow S, Berger A, Cheadle C, Tuder R, Dietz HC, Mitzner W, Wise R, Neptune E
JournalJ Clin Invest
Date Published2012 Jan
KeywordsAngiotensin II Type 1 Receptor Blockers, Animals, Apoptosis, Disease Models, Animal, Humans, Losartan, Lung, Male, Mice, Mice, Inbred AKR, Pulmonary Disease, Chronic Obstructive, Receptor, Angiotensin, Type 1, Respiratory Mechanics, Signal Transduction, Smoking, Transforming Growth Factor beta

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.

Alternate JournalJ. Clin. Invest.
PubMed ID22182843
PubMed Central IDPMC3248282
Grant ListP50HL084945 / HL / NHLBI NIH HHS / United States
R01HL085312 / HL / NHLBI NIH HHS / United States
R03HL095406-01 / HL / NHLBI NIH HHS / United States