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

Megan Podowski, Carla Calvi, Shana Metzger, Kaori Misono, Hataya Poonyagariyagorn, Armando Lopez-Mercado, Therese Ku, Thomas Lauer, Sharon McGrath-Morrow, Alan Berger, Christopher Cheadle, Rubin Tuder, Harry C. Dietz, Wayne Mitzner, Robert Wise, Enid Neptune

Research output: Contribution to journalArticlepeer-review

Abstract

Chronic obstructive pulmonary disease (COPD) is a prevalent smoking-related disease for which no diseasealtering 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.

Original languageEnglish (US)
Pages (from-to)229-240
Number of pages12
JournalJournal of Clinical Investigation
Volume122
Issue number1
DOIs
StatePublished - Jan 3 2012

ASJC Scopus subject areas

  • Medicine(all)

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