Editors' ChoiceChronic Lung Disease

Smoking Out a New Therapy for Lung Disease

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Science Translational Medicine  25 Jan 2012:
Vol. 4, Issue 118, pp. 118ec15
DOI: 10.1126/scitranslmed.3003735

Sometimes a potential new therapeutic is already out there—you just have to look. Chronic obstructive pulmonary disease (COPD), which is a common smoking-related lung disorder that leads to severe cardiopulmonary disease, is the fourth leading cause of death in the United States. Current therapies for COPD ameliorate patient symptoms and minimize complications, but there are no treatments that significantly alter the course of disease. Now, a new study by Podowski et al. provides intriguing preclinical data in a mouse model of cigarette smoke–induced lung disease to show that a drug commonly used to treat high blood pressure may minimize the smoking damage that results in COPD.

Losartan treats high blood pressure by blocking angiotensin receptor type 1, which relieves tightening of blood vessels. However, there is also evidence that losartan may act on transforming growth factor–β (TGF-β) signaling pathways. Because TGF-β dysregulation is thought to contribute to COPD pathogenesis, the authors examined the role of losartan in an animal model of lung injury—emphysema caused by exposure to cigarette smoke. These mice had increased amounts of active TGF-β and downstream markers of TGF-β signaling, including phosphorylated Smad2 (psmad2) and connective tissue growth factor. Lungs of COPD patients had similar increases in psmad2 and TGF-β. Interestingly, exposure of mice to cigarette smoke with concurrent administration of losartan decreased amounts of active TGF-β and psmad2 in the lungs of mice. This effect was accompanied by attenuation in airspace enlargement and improved lung mechanics. In mice treated with a neutralizing TGF-β antibody, the authors observed similar outcomes, suggesting that losartan was acting through TGF-β signaling pathways. Using a transcriptional analysis, Podowski et al. found that losartan normalized levels of the canonical survival kinase Akt, an effect that may have reduced alveolar cell death. In addition, they found that losartan might have helped to decrease airspace enlargement in mice by reducing the activation of metalloproteases, which have been associated with COPD pathogenesis in humans. This study provides promising preclinical evidence that a commonly prescribed drug may unexpectedly have a significant protective effect in COPD and represents an exciting advance should clinical trials confirm these results in patients.

M. Podowski et al., Angiotensin receptor blockade attenuates cigarette smoke–induced lung injury and rescues lung architecture in mice. J. Clin. Invest. 122, 229–240 (2012). [PubMed]

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