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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-? 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-? signaling would protect against CS-induced lung injury. We first confirmed that TGF-? 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-? signaling in CS-exposed mice. Systemic administration of a TGF-?-specific neutralizing antibody normalized TGF-? 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-? signaling, also improved oxidative stress, inflammation, metalloprotease activation and elastin remodeling. These data support our hypothesis that inhibition of TGF-? 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-?-targeted therapies for patients with COPD.

SUBMITTER: Podowski M 

PROVIDER: S-EPMC3248282 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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

Podowski Megan M   Calvi Carla C   Metzger Shana S   Misono Kaori K   Poonyagariyagorn Hataya H   Lopez-Mercado Armando A   Ku Therese T   Lauer Thomas T   McGrath-Morrow Sharon S   Berger Alan A   Cheadle Christopher C   Tuder Rubin R   Dietz Harry C HC   Mitzner Wayne W   Wise Robert R   Neptune Enid E  

The Journal of clinical investigation 20111219 1


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  ...[more]

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