SÓLO A QUIENES HAN UTILIZADO INTERNET EN LOS ÚLTIMOS TRES MESES (1 en P12)

1.7.6.1 Loss of Muscle Mass

A common comorbidity of COPD, which is well established, is the loss of musculoskeletal mass, which manifests as weight loss (Bolton et al., 2004). This is a common clinical manifestation of COPD, and in particular those with emphysema (Engelen et al., 2000b). As the severity of the disease increases, the patient is more prone to loss of weight and low body mass index (BMI). Several studies have shown higher COPD-related mortality rates in underweight and normal weight patients compared to overweight and even obese patients (Landbo et al., 1999, Schols et al., 1998). Such a relationship contrasts with the U-shaped survival curve that is seen for BMI in other population studies (Bray, 1987). This discrepancy is attributed to the fact that BMI does not reliably reflect metabolic change in muscle mass (Rutten et al., 2013).

Fat Free Mass (FFM) has been shown to be a reliable indicator of mortality and prognosis in several studies (Schols et al., 2005, Van Den Borst et al., 2011, Vestbo et al., 2006). Vestbo and co-authors (2006) demonstrated that patients with COPD have some depletion of muscle mass in the presence of a normal or high BMI, and this is inversely related to the severity of the lungs' condition, especially in GOLD stages III and IV. Interestingly, this subgroup of patients, known as having muscle mass loss, are also at increased risk of death, suggesting that FFM is a predictor of mortality independent of BMI (Vestbo et al., 2006).

Loss of FFM adversely affects peripheral and respiratory muscle function, resulting in further respiratory compromise, exercise intolerance and reduced health status (Engelen et al., 1994, Hopkinson et al., 2007). In addition, loss of FFM increases the risk of exacerbation, hospital admission and mortality (Engelen et al., 2000b, Schols et al., 2005). Furthermore, Eisner and colleagues (2007) demonstrated that increased fat mass was strongly associated with activity limitation.

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The underlying mechanism of both weight loss and loss of FFM seems to be complex and remains poorly understood. Nevertheless, various hypotheses have been proposed, which include systemic inflammation, protein metabolism imbalance and deregulation of muscle homeostasis. Bolton et al. (2004) demonstrated that the urinary pseudouridine (PSU), a marker of cellular protein breakdown, is significantly associated with the loss of FFM and particularly in severe and very severe COPD patients.

1.7.6.2 Fat Tissue and Adipokines

Pathophysiological mechanisms linking COPD and development of comorbidities remain largely unknown, but increased systemic inflammation has been suggested to play a role (Vanfleteren et al., 2013). Systemic inflammation has been implicated in the development of musculoskeletal dysfunction, atherosclerosis, osteoporosis and CVD (Eid et al., 2001, Bolton et al., 2004, Sin and Man, 2005). However, the source of inflammation is not fully elucidated. Patients with COPD often have altered body composition. Previously, great interest was shown in loss of FFM and the link to increased mortality. More recently attention has focused on an increased fat mass (FM), even in the presence of a normal FFM, because of it‘s relationship to systemic inflammation, loss of physical function and cardiovascular risk. Adipose tissue is now accepted as an active endocrine organ that produces a variety of pro-inflammatory mediators including interleukin-6, which contributes in the development of insulin resistance and the increased risk of diabetes mellitus and cardiovascular disease in COPD (Barnes and Celli, 2009, Rutten et al., 2010, Watz et a., 2008). Adipose tissue also produces a variety of adipokines, which influence a wide range of bodily physiological systems (Rutten et al., 2010). COPD is associated with intermittent or chronic hypoxemia, which is suggested to lead to adipose tissue hypoxemia and consequently adipose tissue inflammation (Agusti et al., 2010). The most studied adipokines in COPD are adiponectin and leptin. Adiponectin plays a crucial role in

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inhibiting inflammation, improving vascular haemostasis and reducing cardiovascular morbidity and mortality (Sood, 2010, Breyer et al., 2012, Yoon et al., 2013). In contrast, increased levels of leptin are associated with increased local inflammation, oxidative stress and development of CVD (Breyer et al., 2011, Sattar et al., 2006). Adiponectin has a pleiotropic effect and its regulatory role is not fully understood. In a subset of patients from the ECLIPSE study, Breyer and colleagues (2012) have found that patients with COPD demonstrated raised levels of serum adiponectin and were inversely related to BMI compared with age, gender and BMI matched control subjects. They showed the levels of adiponectin were inversely related to CRP and independent of gender. Similar findings have been reported in a small sample size of Chinese COPD population and serum adiponectin increased with the airways severity (Chan et al., 2010). However, unlike the study by Beryer et al. (2012), Chan and colleagues (2010) reported a positive relationship between CRP and serum adiponectin. Contrary to previous studies, in a fair sample sized COPD study, Breyer and co-authors (2011) reported no association between plasma adiponectin and inflammatory biomarkers (i.e. CRP or TNFα) and the levels of serum adiponectin were similar between patients with COPD and age and gender matched controls.

Recently, the longitudinal results from the Lung and Health Study showed increased levels of serum adiponectin were associated with lower hospitalisations and reduced risk of cardiovascular mortality (Yoon et al., 2012). This is supported by a number of clinical studies, which have found increased plasma levels of adiponectin has a cardioprotective role against coronary heart disease, increased risk of myocardial infarction and remodelling of cardiomyocytes after infarction (Sattar et al., 2006). Nevertheless, this study showed other debilitating effects of circulating adiponectin on the lung, where raised levels of plasma adiponectin were associated with bronchial hyperactivity, rapid decline in lung function and doubled the risk of respiratory-related mortality (adjusted hazard ratio, 2.09; 95% CI, 1.41-3.11). Consistent with these

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findings, other studies have reported that increased levels of adiponectin were associated with the severity of airway obstruction and increase the risk of exacerbations (Kirdar et al., 2009, Chan et al., 2010).

Another adipokine that has been studied in COPD populations is leptin. Patients with COPD showed elevated levels of plasma and pulmonary leptin, which were associated with increased inflammation compared with age and gender matched control subjects (Broekhuizen et al., 2005, Beryer et al., 2011). A conflicting result has also been reported in a study by Kirdar and colleagues (2009) who showed patients with COPD and age and gender matched controls had similar levels of serum leptin. Plasma leptin has been shown to be gender and BMI dependent (Breyer et al., 2011). Female patients demonstrated higher levels of leptin than their male counterparts (Breyer et al., 2011). These differences are not fully understood, but may attribute to differences in sex hormones and body fat distribution.

Increased serum and pulmonary leptin and it‘s relationship with other pro- inflammatory biomarkers suggest a potential role for leptin in the pathogenesis of COPD and the increased risk of CVD in this population.

Nevertheless, the role of adipokines in COPD is still controversial due to limited studies and knowledge in this field. Understanding the physiological and pathophysiological role of adipokines in local and systemic inflammation is crucial. Future studies are needed to explore the role of adipokines and their involvement in the disease process.