Bone marrow-derived progenitors are greatly reduced in patients with severe COPD and low-BMI
Introduction
Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation not fully reversible, associated with abnormalities of both airways (bronchitis) and parenchyma (emphysema), reduced exercise tolerance and systemic inflammation (Burrows et al., 1966, Gan et al., 2004, GOLD, 2006). Because of the frequent occurrence of extrapulmonary manifestations, such as weight loss and cachexia, muscle dysfunction, cardiovascular disease and osteoporosis in COPD patients, some authors have suggested that COPD may be considered a systemic disease (Palange et al., 1998, Schols et al., 1998, Biskobing, 2002, Agustí et al., 2003, Sin and Man, 2003).
Recent studies have provided evidence that circulating bone marrow-derived progenitors (CD34+ cells) play an important role in the pathogenesis of several chronic disease states, such as cardiovascular, cerebrovascular, endocrinological, hematological and connective tissue disorders (Blann and Pretorius, 2006). Circulating progenitor counts were found to correlate with disease severity and risk factors (Vasa et al., 2001, Valgimigli et al., 2004), and appear as important cells involved in tissue repair, through neovascularization and reendothelialization (Kocher et al., 2001, Ince et al., 2005, Assmus et al., 2006, Kang et al., 2006). In pulmonary disease, bone marrow appears as a previously unrecognised systemic target of COPD, as suggested by the decreased number of circulating CD34+ cells found in moderate to severe COPD patients, which correlated with hypoxemia, severity of airway obstruction and peak oxygen uptake (Palange et al., 2006). Similarly, circulating CD34+ cells and endothelial progenitors were decreased also in patients with restrictive lung disease (Fadini et al., 2006). Therefore, similar to the effects reported for smoking (van Eeden and Hogg, 2000) and air-pollution (Mukae et al., 2001), a link between systemic inflammation and bone marrow involvement could also be considered in COPD.
Among the extrapulmonary effects of COPD, weight loss seems to be a major systemic feature of the disease. Schols et al. (1998) have demonstrated, in a retrospective study that body mass index (BMI) as well as age and low , are significant independent predictors of increased mortality rates in COPD patients. Similar to BMI, fat-free mass, fat mass and skeletal muscle indexes are considered important prognostic parameters, and a multidimensional grading system, the BODE index, including BMI, airway obstruction, dyspnea and exercise capacity, has been proposed as a predictor of risk of death (Celli et al., 2004). In addition, weight loss appears to negatively affect respiratory and peripheral muscle function and exercise capacity in COPD patients (Palange et al., 1995, Palange et al., 1998).
In COPD patients, the mechanisms underlying weight loss and muscle wasting are not well understood. An imbalance in protein degradation and replacement as well as hormonal changes have been studied: interestingly, proinflammatory cytokines, such as interleukin-1 and tumor necrosis factor-alpha, were found to be associated with hormonal alterations, muscle wasting and cachexia in COPD patients (Wouters et al., 2002). Therefore, a relationship between reduction in body weight and systemic inflammation might be considered and investigated in COPD.
In the present study, we hypothesized that in COPD, in addition to the severity of airflow obstruction, release of bone marrow-derived progenitors into circulation could be more reduced in those patients with greater systemic signs as reflected by low-BMI and high levels of proinflammatory cytokines.
Section snippets
Subjects
Thirty-nine patients with COPD and 12 age-matched nonsmoker subjects (healthy controls) were studied. Inclusion criteria for patients were (1) moderate to very severe COPD (GOLD stages 2–4); (2) stable clinical conditions (i.e. no change in pulmonary function tests or exacerbation in the 4 weeks preceding the study); (3) no other disease as assessed by clinical and standard laboratory findings tests; (4) no disease precluding the performance of the exercise test. No patient received systemic
Nutritional and lung function assessment (Tables 1 and 2)
Table 1 reports anthropometric and pulmonary function data for controls and COPD patients, the latter grouped according to normal-BMI (n = 21; 28 ± 3 kg/m2) and low-BMI (n = 18; 20 ± 2 kg/m2). Measurement of FFM and FFMI confirmed that FFMI was in the normal range (18 ± 3 kg/m2) in the normal-BMI group, whereas FFMI was abnormally low in low-BMI patients (12 ± 4 kg/m2, p = 0.05 versus controls the normal-BMI group).
Compared to the normal-BMI group, low-BMI patients showed a more pronounced pulmonary impairment
Discussion
Our findings show, for the first time, that in COPD patients the bone marrow involvement is related not only to lung function impairment, but also to poor nutritional state and levels of systemic inflammation.
In this study, patients with low-BMI had: greatly reduced circulating hemopoietic and endothelial progenitor counts, suggesting lower progenitor release from the bone marrow; pronounced systemic inflammation with high levels of proangiogenetic growth factors (VEGF-A, VEGF-C and HGF) and
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