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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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Research Article Development

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

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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.

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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Figure 1

Chronic CS induces TGF-β expression in murine lungs and human COPD lungs.

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Chronic CS induces TGF-β expression in murine lungs and human COPD lungs...
(A) TGF-β induction profile by ELISA analysis in lung lysates from AKR/J mice exposed to 2 weeks of CS. *P < 0.01, CS versus RA or CS plus losartan (Los) versus CS. n = 3–5 mice per treatment group. (B) Representative histologic sections of lungs from mice exposed to RA or chronic CS subjected to immunohistochemical staining for psmad2. The inset shows localized staining in alveolar epithelial cells of CS-exposed mice. Arrowheads denote the site of enhanced staining in airspace (AS) walls of patients with COPD. Original magnification, ×20. n = 4–8 mice per treatment group. (C) Quantitative immunohistochemistry of psmad2 staining in RA- and CS-exposed mice depicted in B. (D) Representative immunohistochemical staining for total TGF-β1 in lung sections from a patient with COPD and a control smoker. Original magnification, ×40. Scale bar: 100 μm. n = 10 each of control and COPD tissue sections. LAP-TGF-β1, latency-associated peptide TGF-β complex. (E) Active TGF-β levels in lung lysates from control nonsmokers (Ctrl –Tob) (n = 8), control smokers (Ctrl +Tob) (n = 6), and smokers with moderate COPD (COPD +Tob) (n = 11). (F) Representative immunohistochemical staining for psmad2 in lung sections from a patient with moderate COPD and a control smoker (airspace [2 right panels], airway [left panel]). (G) Quantitative immunohistochemical staining of psmad2 in airspace compartment and airway compartment in lung sections from patients with moderate COPD and smoking controls normalized to tissue area. n = 6–11 in each group. AW, airway.

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