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Angiotensin receptor blockade attenuates cigarette smoke–induced lung injury and rescues lung architecture in mice
Megan Podowski, … , Robert Wise, Enid Neptune
Megan Podowski, … , Robert Wise, Enid Neptune
Published December 19, 2011
Citation Information: J Clin Invest. 2012;122(1):229-240. https://doi.org/10.1172/JCI46215.
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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-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.

Authors

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

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Angiotensin receptor blockade in pulmonary emphysema

Submitter: Stefan Andreas | sandreas@lungenfachklinik-immenhausen.de

Authors: Stefan Andreas, Tobias Raupach, Harald Kögler, Gerd Hasenfuß

Universitätsmedizin Göttingen

Published July 10, 2012

Dear Professor Howard Rockman,

With the greatest interest we have read the recent work by Podowski and coworkers published in the Journal of Clinical Investigation in 2012 (1). This elegant and insightful study investigated angiotensin receptor blockade (ARB) in mice with cigarette smoke induced pulmonary emphysema. Clear beneficial effects of ARB with Losartan were noted and the underlying mechanism, including TGF-ß signaling was comprehensively explored. The authors pointed out that their data substantiate our placebo controlled clinical trial with 4 months of Irbesartan in 60 patients with chronic obstructive pulmonary disease (COPD) showing significant improvement in lung overinflation (2). We completely agree with Podowski et al. who extend our findings in emphysematous mice (3) - not referenced by the authors - by suggesting a molecular mechanism through which ARB exert its beneficial effects. In 2011 we have published a randomized controlled study examining the effects of ARB in a mouse model of severe emphysema elicited by repetitive intratracheal elastase application (3). ARB with irbesartan for 8 weeks resulted in less emphysema (i.e. a lower mean linear intercept: 91 ± 4 μm vs. 122 ± 8 μm; p < 0.005), improved static compliance (163 ± 48 vs 354 ± 61 μl/cm H2O; p=0.04) and improved elastic recoil (time constant Tau 1,9 vs 4,5 sec; p=0.04). Furthermore irbesartan treatment elicited a significant improvement of running distance (p < 0.002). Thus, for the first time we have demonstrated clinical relevant positive effects of ARB in a lung injury model resembling COPD.

Again we would like to congratulate the authors demonstrating for the first time the molecular mechanism through which ARB exert positive effects in COPD.
Yours sincerely,
Stefan Andreas
Tobias Raupach
Harald Kögler
Gerd Hasenfuß

References

  1. Podowski, M., Calvi, C., Metzger, S., Misono, K., Poonyagariyagorn, H., Lopez-Mercado, A., Ku, T., Lauer, T., McGrath-Morrow, S., Berger, A., et al. Angiotensin receptor blockade attenuates cigarette smoke-induced lung injury and rescues lung architecture in mice. J Clin Invest 122:229-240.
  2. Andreas, S., Herrmann-Lingen, C., Raupach, T., Luthje, L., Fabricius, J.A., Hruska, N., Korber, W., Buchner, B., Criee, C.P., Hasenfuss, G., et al. 2006. Angiotensin II blockers in obstructive pulmonary disease: a randomised controlled trial. Eur Respir J 27:972-979.
  3. Raupach, T., Lüthje, L., Kögler, H., Duwe, C., Schweda, F., Hasenfuß, G., and Andreas, S. 2011 Effects of angiotensin II type 1 receptor blockade on pulmonary and systemic manifestations in an emphysema mouse model. Pulm Pharmac Ther 24:215-220.

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