Angiotensin receptor blockade attenuates cigarette smoke–induced lung injury and rescues lung architecture in mice
| Autor: | Enid Neptune, Kaori Misono, Christopher Cheadle, Hataya Poonyagariyagorn, Armando Lopez-Mercado, Megan Podowski, Alan E. Berger, Therese Ku, Wayne Mitzner, Rubin M. Tuder, Sharon A. McGrath-Morrow, Thomas Lauer, Robert A. Wise, Harry C. Dietz, Shana Metzger, Carla L. Calvi |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Angiotensin receptor Apoptosis Lung injury Losartan Receptor Angiotensin Type 1 Alveolar cells Mice Mice Inbred AKR Pulmonary Disease Chronic Obstructive Transforming Growth Factor beta Fibrosis medicine Animals Humans Lung COPD biology business.industry Smoking General Medicine Transforming growth factor beta respiratory system medicine.disease respiratory tract diseases Disease Models Animal medicine.anatomical_structure Immunology Respiratory Mechanics biology.protein business Angiotensin II Type 1 Receptor Blockers Research Article Signal Transduction medicine.drug |
| Zdroj: | Journal of Clinical Investigation. 122:229-240 |
| ISSN: | 0021-9738 |
| DOI: | 10.1172/jci46215 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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