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

      The Journal of clinical investigation
      Angiotensin II Type 1 Receptor Blockers, pharmacology, Animals, Apoptosis, drug effects, Disease Models, Animal, Humans, Losartan, Lung, pathology, physiopathology, Male, Mice, Mice, Inbred AKR, Pulmonary Disease, Chronic Obstructive, etiology, prevention & control, Receptor, Angiotensin, Type 1, metabolism, Respiratory Mechanics, Signal Transduction, Smoking, adverse effects, Transforming Growth Factor beta, antagonists & inhibitors

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          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.

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