Preclinical murine models of Chronic Obstructive Pulmonary Disease

European Journal of Pharmacology 759 (2015) 265–271

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European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar

Preclinical murine models of Chronic Obstructive Pulmonary Disease Ross Vlahos a,b,n, Steven Bozinovski a,b a b

School of Health Sciences, Health Innovations Research Institute, RMIT University, PO Box 71, Bundoora, VIC 3083, Australia Lung Health Research Centre, Department of Pharmacology & Therapeutics, The University of Melbourne, Parkville, VIC 3010, Australia

art ic l e i nf o

a b s t r a c t

Article history: Received 15 November 2014 Received in revised form 3 February 2015 Accepted 12 March 2015 Available online 24 March 2015

Chronic Obstructive Pulmonary Disease (COPD) is a major incurable global health burden and is the 4th 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. & 2015 Elsevier B.V. All rights reserved.

Keywords: AECOPD Comorbidities COPD Emphysema Lung inflammation

1. Introduction Chronic Obstructive Pulmonary Disease (COPD) is a major incurable global health burden and is the 4th leading cause of death worldwide (WHO, 2014). COPD is a “disease characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of lungs to noxious particles and gases” (Pauwels et al., 2001) (Fig. 1). Cigarette smoking is the major cause of COPD and accounts for more than 95% of cases in industrialized countries (Barnes et al., 2003), but other environmental pollutants are important causes in developing countries (Dennis et al., 1996). COPD encompasses chronic obstructive bronchiolitis with fibrosis and obstruction of small airways, and emphysema with enlargement of airspaces and destruction of lung parenchyma, loss of lung elasticity, and closure of small airways. Most patients with COPD have all three pathologic conditions (chronic obstructive n Corresponding author at: School of Health Sciences, Health Innovations Research Institute, RMIT University, PO Box 71, Bundoora, VIC 3083, Australia. Tel.: þ 61 3 9925 7362; fax: þ61 3 9925 6539. E-mail address: [email protected] (R. Vlahos).

http://dx.doi.org/10.1016/j.ejphar.2015.03.029 0014-2999/& 2015 Elsevier B.V. All rights reserved.

bronchiolitis, emphysema and mucus plugging), but the relative extent of emphysema and obstructive bronchiolitis within individual patients can vary. As the disease worsens, patients experience progressively more frequent and severe exacerbations, which are due to viral and bacterial chest infections (Hurst et al., 2010; Rohde et al., 2003; Seemungal et al., 2001; Sethi, 2004) (Fig. 1). Patients are also increasingly disabled by disease comorbidities, such as cardiovascular disease and skeletal muscle wasting, which further reduce their quality of life (Barnes and Celli, 2009; Cavailles et al., 2013; Maltais et al., 2014). In addition, respiratory infections can worsen these comorbidities and further impact on the patient's life (Cavailles et al., 2013). Current forms of therapy for COPD are relatively ineffective and the development of effective treatments for COPD have been severely hampered as the mechanisms and mediators that drive the induction and progression of chronic inflammation, emphysema, altered lung function, defective lung immunity, musculoskeletal derangement and markedly worsened cardiovascular risk remain only poorly understood. Given that cigarette smoke is the major cause of COPD, “smoking mouse” models that accurately reflect disease pathophysiology have been developed and have made rapid progress in identifying candidate pathogenic mechanisms and new therapies (reviewed in

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Pollutants Bacteria Virus

Lung inflammation Cytokines, chemokines, proteases (e.g. GM-CSF, IL-17A, MMP-12) Oxidative stress (e.g. O2•-, H2O2) Cell & tissue injury Airflow limitation “Spill over” Emphysema Systemic inflammation (e.g. IL-6, IL-1β, SAA)

Systemic comorbidities (e.g. skeletal muscle wasting, cardiovascular disease)

Disease progression

Disease progression

DEATH

Fig. 1. General model of cigarette smoke-induced lung inflammation and damage. Increased oxidative stress and lung inflammation in response to cigarette smoke, pollutants and respiratory pathogens causes a spill-over of cytokines into the systemic circulation. Systemic inflammation leads to skeletal muscle wasting initiating and/or worsening co-morbid conditions such as cardiovascular disease. Viral and bacterial pathogens markedly increase systemic inflammation and hence exacerbate COPD and its co-morbidities. Increased lung inflammation and oxidative stress causes cell and tissue injury, airflow limitation, emphysema and ultimately death.

Churg et al. (2008), Fricker et al. (2014), Goldklang et al. (2013), Mercer et al. (2015), Stevenson and Belvisi (2008), Stevenson and Birrell (2011), Vlahos and Bozinovski (2014), Vlahos et al. (2006a), Wright and Churg, (2010), and Wright et al. (2008)).

2. Modelling COPD in mice COPD is a heterogenous disorder consisting of lung inflammation, emphysema, chronic obstructive bronchiolitis and mucus plugging. Animal models play a vital role in determining the underlying mechanisms of COPD as they address questions involving integrated whole body responses. In addition, animal models that accurately reflect disease pathophysiology are key in the drug discovery process as they allow for testing of potential therapeutics. To date, many species have been used including rodents, dogs, guinea-pigs, monkeys and sheep (reviewed in Churg et al. (2008), Wright and Churg (2010) and Wright et al. (2008)). However, mice have been the most popular choice by many investigators given the enormous information about the mouse genome, the abundance of antibody probes, the ability to produce animals with genetic modifications that shed light on specific processes within COPD, the availability of numerous naturally occurring mouse strains with different reactions to smoke and ultimately the low cost. The characteristic features of human COPD can be modeled in mice by exogenous administration of proteases, chemicals, particulates and exposure to cigarette smoke (reviewed in Fricker et al. (2014), Mercer et al. (2015) and Vlahos and Bozinovski (2014)). However, given that cigarette smoke is the major cause of COPD, much work has centered around the cellular and molecular responses triggered by cigarette smoke using either nose only or whole body smoke exposure systems (Beckett et al., 2013; Brusselle et al., 2006; Churg et al., 2002, 2003, 2004, 2008, 2012a, 2012b; Duong et al., 2010; Eltom et al., 2011; Marwick et al., 2009; Morris et al., 2008; Vlahos et al., 2006b; Wan et al.,

2010; Wright and Churg, 2002, 2010; Wright et al., 2008; Yao et al., 2010, 2012). Regardless of the method of exposure, many of the of the characteristic features of human COPD, namely (i) chronic lung inflammation; (ii) impaired lung function; (iii) emphysema; (iv) mucus hypersecretion; (v) small airway wall thickening and remodeling; (vi) vascular remodeling; (vii) lymphoid aggregates and (viii) pulmonary hypertension can be mimicked in the “smoking mouse model”. However, it should be noted that chronic bronchitis cannot be modelled in mice nor the severe disabling disease observed in GOLD stage 3–4. Given the laborious nature of chronic cigarette smoke-exposure protocols, many groups have adopted acute cigarette smoke exposure protocols (1–4 days) to explore the mediators and mechanisms involved in the induction of cigarette smokeinduced lung inflammation (reviewed in Mercer et al. (2015), Vlahos and Bozinovski (2014) and Vlahos et al. (2006a)). These acute protocols have identified a number of mediators including transcription factors (e.g. NFκB), cytokines (e.g. TNFα, IL-1β), proteases (e.g. MMP-9, MMP-12), chemokines (e.g. GM-CSF, IL-17A) and vascular adhesion molecule E selectin (reviewed in Mercer et al. (2015) and Vlahos and Bozinovski (2014)). In addition, this “high throughput screen” approach has often been used to identify potential therapeutic targets which are then taken in to more chronic models of experimental COPD. Chronic cigarette smoke protocols have largely been used to explore the mechanisms that drive chronic inflammation, impaired lung function, emphysema, small airway wall thickening and remodeling and vascular remodeling (reviewed in Fricker et al. (2014) and Mercer et al. (2015)). For example, these studies have shown that matrix metalloproteases (e.g. MMP-12), neutrophil elastase, cytokines (TNF-α IL-1β), cytokine receptors (TNFR I and II), chemokines (IL-17A), chemokine receptors (e.g. CCR5 and CCR6), myeloperoxidase and oxidative stress are involved in the development of chronic lung inflammation and emphysema (reviewed in Fricker et al. (2014) and Mercer et al. (2015)). Chronic

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smoke exposure protocols have also been used to explore genetic control of cigarette smoke-induced lung inflammation and emphysema (Guerassimov et al., 2004; Mahadeva and Shapiro, 2002). It has been shown that several inbred strains of mice develop emphysema spontaneously due to genetic abnormalities (Mahadeva and Shapiro, 2002) and genetic manipulation itself can result in emphysema either spontaneously or during development (Cavarra et al., 2001; Ernst et al., 2002; Mahadeva and Shapiro, 2002; Ruwanpura et al., 2011; Shapiro et al., 2004). Recent advances in lung function measurements and imaging have also been used to detect lung dysfunction in mice chronically exposed to cigarette smoke before CT detection of structural changes and can provide a non-invasive method for longitudinally studying lung dysfunction in preclinical models (Jobse et al., 2013).

3. Modelling acute exacerbations of COPD An acute exacerbation of COPD (AECOPD) is defined as “a sustained worsening of the patient's condition, from the stable state and beyond normal day to day variation, which is acute in onset and necessitates change in regular medication in a patient with underlying COPD” (Mackay and Hurst, 2013). Exacerbations are a common occurrence in COPD patients and contribute mainly to morbidity, death and health-related quality of life (Mackay and Hurst, 2013). AECOPD is a major cause of avoidable hospital admissions and often due to viral and bacterial infections with 40–60% attributed to viral infections alone (Mackay and Hurst, 2013). The majority of these infections are due to respiratory syncytial virus (22%), influenza A (25%) and picornavirus (36%), with influenza having the potential to be more problematic due to the likelihood of an epidemic (Mackay and Hurst, 2013; Rohde et al., 2003; Seemungal et al., 2001). Respiratory viruses produce longer and more severe exacerbations and have a major impact on health care utilization (Seemungal et al., 2001, 2000). Currently bronchodilator combinations reduce the risk of exacerbation by about 30% but there are no specific or effective therapies to treat AECOPD itself and the mechanisms underlying AECOPD are poorly understood (Mackay and Hurst, 2013). The cellular and molecular mechanisms underlying AECOPD are poorly understood, but there is an increase in neutrophils and concentrations of IL-6, IL-8, TNF-α and LTB4 in sputum during an exacerbation (Aaron et al., 2001; Crooks et al., 2000) and patients who have frequent exacerbations have higher levels of IL-6 and lower concentrations of SLPI, even when COPD is stable (Bhowmik et al., 2000; Gompertz et al., 2001a). There is also an increase in the activation of NFκB in alveolar macrophages during exacerbations of COPD (Caramori et al., 2003). The contribution of oxidative stress in AECOPD has also been recognized (Aoshiba et al., 2001; Dekhuijzen et al., 1996; Hoshino et al., 2001; Loukides et al., 2011; Nowak et al., 1996). There is an increased concentration of H2O2 in exhaled breath condensate of AECOPD patients compared to patients with COPD (Dekhuijzen et al., 1996; Nowak et al., 1996). H2O2 can activate NFκB resulting in pro-inflammatory gene activation, thereby worsening the condition (de Oliveira-Marques et al., 2007; Rahman and Adcock, 2006). Given the important role of viruses in COPD, we and others have developed in vivo models to investigate the impact of viral infection on cigarette smoke-exposed mice (reviewed in Mercer et al. (2015), Starkey et al. (2013) and Vlahos and Bozinovski (2014). The advantage of these models is the use of live, replication competent viruses rather than replication deficient adenovirus. We have previously shown that compared to smoke or influenza (H3N1, Mem71 strain) alone, male Balb/c mice exposed to cigarette smoke for 4 days and then influenza had more BALF inflammation (macrophages, neutrophils, virus-specific CD8þ T lymphocytes),

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altered lung profiles of key cytokines, worse lung pathology and higher lung virus titres (Gualano et al., 2008). In addition, when smoking ceased after viral infection, smoke and influenza mice regained significantly less weight than smoke alone mice (Gualano et al., 2008). Increased pulmonary inflammation following influenza infection in both acute (4 days) (Bauer et al., 2010; Botelho et al., 2011; Yageta et al., 2011) and chronic (3–6 months) (Robbins et al., 2006; Wortham et al., 2012) cigarette smoke exposure protocols have also been reported by others, but using different strains of influenza A virus (H1N1, A/FM/1/47; H1N1, A/PR/8/34; H3N2, HKx31)) and mice. However, a recent study showed that the pathogenicity of both swine-origin pandemic influenza A virus (pdmH1N1) and avian H9N2 influenza A virus was alleviated in cigarette smoke-exposed mice, which might partially be attributed to the immunosuppressive effect of nicotine (Han et al., 2014). Overall, the majority of published studies demonstrate that cigarette smoke exacerbates the inflammatory response to influenza A virus and that these mouse models may be useful in studying how smoke worsens respiratory viral infections. As live viruses often require special containment facilities and can be difficult to work, some groups have used polyinosinicpolycytidylic acid (poly(I:C)) as a surrogate to simulate viral infections and to model AECOPD. Elias and colleagues have shown that cigarette smoke enhanced parenchymal and airway inflammation and apoptosis induced by poly(I:C) in mice and that cigarette smoke and poly(I:C) accelerated the development of emphysema and airway fibrosis (Kang et al., 2008; Zhou et al., 2013). It has also recently been shown that cigarette smoke exposure exacerbated poly(I:C)-induced neutrophilia (Hubeau et al., 2013; Kimura et al., 2013) and airway hyper responsiveness (Kimura et al., 2013) in mice.

4. Modelling co-infections in COPD As approximately 50% of COPD patients are chronically colonized with potentially pathogenic microorganisms including Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis (Monso et al., 1995; Pela et al., 1998), it is not unusual to detect both a viral and bacterial pathogen during an exacerbation. Bacterial infections are also a common cause of purulent AECOPDs associated with a marked increase in airway (Gompertz et al., 2001b) and systemic inflammation (Sethi et al., 2008). Coinfection with virus and bacteria has been reported in approximately 10% of exacerbations (Wark et al., 2013), although this may be more frequent as the cross-sectional nature of sampling in the limited number of studies that report co-infection may not capture the full sequel of events. Co-infection during AECOPD was associated with an increase level of systemic inflammation (Bozinovski et al., 2008). In addition, the presence of co-infection during an exacerbation leads to greater exacerbation severity, to suggest that bacterial and viral pathogens interact to cause worse outcomes during an AECOPD (Wilkinson et al., 2006). Viral infection has also been shown to degrade antimicrobial peptides as a consequence of increased protease activity in the airways, which led to secondary bacterial infection in COPD (Mallia et al., 2012). Hence there is a need to develop better models that recapitulate co-infection in the context of COPD. There are multiple murine models of viral-induced secondary bacterial infection, which differ in timing and combination of pathogen delivery. A common mechanism for impaired host defense during coinfection involves the production of interferon production during the recovery phase of a viral infection, which has been shown to compromise lung anti-bacterial defenses. Viralinduced production of interferon-γ has been shown to downregulate the scavenger receptor MARCO, and neutralization of

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interferon-γ prevented secondary pneumococcal infection (Sun and Metzger, 2008). Using MARCO-deficient mice, it has been established that expression of this scavenger receptor on alveolar macrophages (AMs) is critical for efficient clearance of Streptococcus pneumoniae (Spn) from the lungs (Arredouani et al., 2004). In addition, the initial depletion of AMs as a consequence of influenza infection renders the host susceptible to Spn colonization and systemic invasion (Ghoneim et al., 2013). This AM depletion phase may represent a window of opportunity for respiratory pathogens such as Spn, which take advantage of this immunocompromised state. It is intriguing to speculate that increased susceptibility to viral exacerbations also renders COPD patients at much greater risk of community acquired pneumonia (CAP), as rates of CAP are significantly higher in elderly subjects with obstructive lung disease. Since co-infection is more frequent in COPD, the development of better models is needed as the interaction between virus and bacteria are likely to have a dramatic impact on essential immunological processes. The development of such models may shed further light into our understanding of how coinfection may drive worse outcomes during AECOPD, and may also reveal important insight into why bacterial colonization and CAP are much higher in COPD.

5. Modelling systemic comorbidities of COPD COPD is often associated with systemic comorbidities that can impact on the patient's functional capacity, quality of life, and also increase the risk of hospitalization and mortality in COPD patients (Barnes and Celli, 2009; Cavailles et al., 2013). These comorbidities include skeletal muscle wasting (cachexia), cardiovascular disease, lung cancer, osteoporosis and diabetes (Barnes and Celli, 2009; Cavailles et al., 2013). It is currently not clear whether these comorbidities are independent co-existing conditions (as a result of the advanced age or smoking history of the patient) or a consequence of the patients' COPD. Given that comorbidities have a profound impact on COPD patients, much research has now focused on developing preclinical mouse models of systemic comorbidities associated with COPD to determine the mechanisms underlying these conditions and to ultimately identify novel therapeutic options for these patients. 5.1. Skeletal muscle wasting Skeletal muscle wasting (or cachexia) occurs in approximately 25% of patients with COPD and is a powerful predictor of mortality in COPD (Maltais et al., 2014; Schols et al., 1998). The disability associated with skeletal muscle wasting is due to both loss of strength and endurance (Allaire et al., 2004; Gosker et al., 2002; Maltais et al., 2000). In addition, rapid deteriorations in lean muscle mass have been described following acute exacerbations of COPD and muscle weakness is more pronounced during an exacerbation (Maltais et al., 2014; Spruit et al., 2003). Although some mechanisms underlying the development of skeletal muscle dysfunction have been identified (e.g., deconditioning), much needs to be learned about the impact of other potential contributors to limb muscle dysfunction in COPD (e.g., inflammation, malnutrition, oxidative stress and hypoxemia) which themselves could be novel therapies to address this problem (reviewed in Maltais et al. (2014)). We have accordingly in parallel developed sophisticated and refined preclinical models of skeletal muscle wasting in mice through iterative clinical cross-validation. Using these models we have shown that mice exposed chronically (4–6 months) to cigarette smoke had increased BALF inflammation, peripheral

airspace enlargement, impaired lung function and had reduced body weight, fat mass, hind limb skeletal muscles mass (gatrocnemius, tibialis anterior, soleus), grip strength (index of muscle strength) and aerobic endurance (Chen et al., 2005, 2006, 2007; Hansen et al., 2007, 2013, 2006). Cigarette smoke altered the mRNA expression of a number of genes associated with the regulation of skeletal muscle mass including insulin-like growth factor-I, atrogin-1, MuRF-1 and IL-6 (Hansen et al., 2007, 2013). Interestingly, Caron et al. (2013) recently showed that a 60-day smoking cessation period reversed the skeletal muscle (gastrocnemius and soleus) cell signalling alterations induced by 8–24 weeks of cigarette smoke exposure. Others have shown that mice exposed to cigarette smoke for 6 months had increased circulating levels of the pro-inflammatory cytokine TNF-α and that the oxidative fiber type IIA proportion was significantly reduced in the soleus (Gosker et al., 2009). Tang et al. (2010) also found that mice exposed to cigarette smoke (daily for 8 or 16 weeks) had elevated serum TNF-α, and that this was accompanied by loss of body and gastrocnemius complex mass, with rapid soleus fatigue and diminished exercise. It has also been reported that compared with air-exposed mice, skeletal muscles from cigarette smokeexposed (6 months) mice had reduced muscle fiber cross-sectional area, decreased skeletal muscle capillarization, and reduced exercise tolerance (Basic et al., 2012). Using a nose-only exposure system, Beckett et al. (2013) found that mice had decreased quadriceps mass only after 8 weeks of cigarette smoke exposure whereas Rinaldi et al. (2012) found that muscular changes became apparent only after 6 months of cigarette smoke exposure, particularly in muscles with a mixed fiber-type composition. Thus, the above studies highlight that chronic cigarette smoke exposure results in systemic features that closely resemble extrapulmonary manifestations observed in patients with COPD, and that these murine models can be used to explore therapeutics aimed at treating skeletal muscle wasting and dysfunction observed in human COPD. 5.2. Cardiovascular disease It is now apparent that patients with COPD have an increased risk of cardiovascular disease and thus are at greater risk of dying from cardiovascular causes (Barnes and Celli, 2009; Bhatt and Dransfield, 2013; Bhatt et al., 2014). Studies have reported that up to 40% of deaths in COPD patients is due to cardiovascular disease (Berger et al., 2004; Chatila et al., 2008; Sin and Paul Man, 2005; Sin et al., 2005) and more people with mild to moderate COPD die of cardiovascular causes than of respiratory failure (Bhatt et al., 2014). Specifically, patients with COPD have a significantly higher risk of acute myocardial infarction (MI), arrhythmia and congestive heart failure (Curkendall et al., 2006). Over 5 years of follow-up and compared with patients without COPD, patients with COPD had higher rates of death, MI, stroke and a higher rate of hospitalization due to heart failure, unstable angina, or arterial revascularization (de Barros et al., 2014). It has also been demonstrated that cardiovascular risk is even more pronounced, and has a greater effect, during the peri-exacerbation period due to further increases in pulmonary and systemic inflammation. One to five days after a severe exacerbation, the risk of MI increases 2–3 times (Donaldson et al., 2010) and subclinical ischemia might be even more common during these events, as well as during exacerbations of only moderate severity (Patel et al., 2013). Therefore, there has been intense research to develop clinically-relevant animal models to investigate the link between COPD and cardiovascular comorbidities. Recently, it has been shown that chronic cigarette smoke exposure enlarged ventricular end systolic and diastolic diameters, reduced myocardial and cardiomyocyte contractile function and disrupted intracellular Ca2 þ homeostasis, and facilitated fibrosis, apoptosis and

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mitochondrial damage (Hu et al., 2013). Sussan et al. (2009) also showed that mice chronically exposed to cigarette smoke that had chronic lung inflammation and emphysema had pulmonary hypertensinon and significant impairments to right ventricle diastolic and systolic function and contractility. In addition, Beckett et al. (2013) found that hearts from mice exposed to cigarette smoke for 8 weeks that had pulmonary impairments were significantly larger and heavier than air-exposed mice. Moreover, Talukder et al. (2011) showed that chronic cigarette smoking causes hypertension, endothelial dysfunction and cardiac remodeling in mice. Smoke exposure induced RV systolic dysfunction demonstrated by reduced tricuspid annular plane systolic excursion (Hassel et al., 2014). 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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