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

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
The Journal of clinical investigation (Impact Factor: 13.22). 12/2011; 122(1):229-40. DOI: 10.1172/JCI46215
Source: PubMed


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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    • "Of interest is that drugs that impact on the cardiovascular system (e.g. statins, angiotensin II blockers) have recently been shown in animal models to protect against cigarette smoke-induced lung inflammation, emphysema and pulmonary hypertension and may therefore provide an important therapeutic benefit for COPD patients (Lee et al., 2005; Podowski et al., 2012; Wright et al., 2011). In addition, it has recently been shown that high intensity interval training in smoke-exposed mice reversed right ventricular dysfunction and reduced pulmonary vessel remodeling suggesting that exercise training has important effects on the heart and pulmonary vasculature (Hassel et al., 2014). "
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    ABSTRACT: Chronic Obstructive Pulmonary Disease (COPD) is a major incurable global health burden and is the 4(th) leading cause of death worldwide. It is believed that an exaggerated inflammatory response to cigarette smoke causes progressive airflow limitation. This inflammation, where macrophages, neutrophils and T lymphocytes are prominent, leads to oxidative stress, emphysema, small airway fibrosis and mucus hypersecretion. Much of the disease burden and health care utilisation in COPD is associated with the management of its comorbidities and infectious (viral and bacterial) exacerbations (AECOPD). Comorbidities, defined as other chronic medical conditions, in particular skeletal muscle wasting and cardiovascular disease markedly impact on disease morbidity, progression and mortality. The mechanisms and mediators underlying COPD and its comorbidities are poorly understood and current COPD therapy is relatively ineffective. Thus, there is an obvious need for new therapies that can prevent the induction and progression of COPD and effectively treat AECOPD and comorbidities of COPD. Given that access to COPD patients can be difficult and that clinical samples often represent a "snapshot" at a particular time in the disease process, many researchers have used animal modelling systems to explore the mechanisms underlying COPD, AECOPD and comorbidities of COPD with the goal of identifying novel therapeutic targets. This review highlights the mouse models used to define the cellular, molecular and pathological consequences of cigarette smoke exposure and the recent advances in modelling infectious exacerbations and comorbidities of COPD. Copyright © 2015. Published by Elsevier B.V.
    European journal of pharmacology 03/2015; 759. DOI:10.1016/j.ejphar.2015.03.029 · 2.53 Impact Factor
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    • "In addition, TGF-β receptors are suggested to play a significant role in the pathogenesis of COPD through their regulation of TGF-β/Smads pathways. A previous study suggests that pharmacologic inhibition of TGF-β signaling can protect the murine lung from altered lung histology, impaired lung function and a panel of injury measures that accompany cigarette smoke-induced COPD [5]. "
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    ABSTRACT: The three Tiao-Bu Fei-Shen (Bufei Jianpi, Bufei Yishen, Yiqi Zishen) granules have been confirmed for their beneficial clinical efficacy in chronic obstructive pulmonary disease (COPD) patients on reducing frequency and duration of acute exacerbation, improving syndromes, pulmonary function and exercise capacity. But the short- or long-term mechanism of them is not fully clear. Nuclear factor (NF)-kappaB/transforming growth factor (TGF)-beta1/smad2 signaling pathway is involved in the progress of inflammation and remodeling in chronic obstructive pulmonary disease COPD. This study aimed to explore the long-term effects mechanism of Tiao-Bu Fei-Shen granules by regulating NF-kappaB/TGF-beta/Smads signaling in rats with COPD. Sprague Dawley rats were randomized into control, model, Bufei Jianpi, Bufei Yishen, Yiqi Zishen and aminophylline groups. COPD rats, induced by cigarette smoke and bacterial infections exposures, were administrated intragastricly by normal saline, Bufei Jianpi, Bufei Yishen, Yiqi Zishen granules or aminophylline from week 9 through 20, respectively. At week 20 and 32, lung tissues were harvested. Immunohistochemistry was used to detect interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha, quantitative real-time polymerase chain reaction (qRT-PCR) was used for TGF-beta1 and Smad2 mRNA analysis, western blotting was used to determine the phosphorylation of NF-kappaB (p-NF-kappaB) and IkappaBalpha (p-IkappaBalpha). COPD rats had marked airway injury, such as chronic airway inflammation and remodeling, emphysema, which were improved in the three traditional Chinese medicines (TCM)-treated animals. The levels of IL-1beta, TNF-alpha, p-NF-kappaB, p-IkappaBalpha, TGF-beta1 and Smad2 were significantly higher in COPD rats than in controls, while they were dramatically reduced in the three TCM- and aminophylline-treated groups. At the meantime, all these endpoints were significantly lower in three TCM-treated groups than in aminophylline group, especially in Bufei Jianpi and Bufei Yishen groups. Compared to week 20, all endpoints decreased significantly in three TCM groups at week 32. The three Tiao-Bu Fei-Shen therapies can reduce pulmonary inflammation and remodeling in COPD and have significant long-term effects. NF-kappaB/TGF-beta1/smad2 signaling might be involved in the mechanism.
    BMC Complementary and Alternative Medicine 04/2014; 14(1):140. DOI:10.1186/1472-6882-14-140 · 2.02 Impact Factor
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    • "Nrf2, a regulator of the antioxidant pathway, also plays a major role in determining susceptibility to smoke-induced emphysema by upregulating antioxidants and thereby decreasing inflammation (Rangasamy et al., 2004, 2009; Iizuka et al., 2005; Gebel et al., 2010). Additionally, the TGF-β signaling pathway influences oxidative stress in the setting of smoke exposure; antagonism of this pathway with the angiotensin receptor type 1 blocker losartan decreased oxidative stress, inflammation and extracellular matrix remodeling (Podowski et al., 2012). Furthermore, the class III histone/protein deacetylase SIRT1 regulates cigarette smoke-exposure mediated proinflammatory signaling through NF-kappa-B and levels are decreased in rats following smoke exposure (Yang et al., 2007). "
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    ABSTRACT: Exposure to second hand smoke is a major cause of chronic obstructive pulmonary disease (COPD) in the non-smoker. In this review we explore the use of animal smoke exposure models and their insight into disease pathogenesis. The methods of smoke exposure, including exposure delivery systems, are described. Key findings from the acute and chronic smoke exposure models are outlined, including descriptions of the inflammation processes, proteases involved, oxidative stress, and apoptosis. Finally, alternatives to rodent models of lung disease are presented.
    Frontiers in Physiology 02/2013; 4:30. DOI:10.3389/fphys.2013.00030 · 3.53 Impact Factor
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