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Keywords:

  • immune response;
  • oxidative stress;
  • myokine

Abstract

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. Perspective
  7. Acknowledgements
  8. Funding
  9. References

Systemic inflammation in patients with chronic obstructive pulmonary disease (COPD) has been related to the development of comorbidities. The level of systemic inflammatory mediators is aggravated as a response to exercise in these patients. The aim of this study was to investigate whether unloading of the respiratory muscles attenuates the inflammatory response to exercise in COPD patients. In a cross-over design, eight muscle-wasted stable COPD patients performed 40 W constant work-rate cycle exercise with and without non-invasive ventilation support (NIV vs control). Patients exercised until symptom limitation for maximally 20 min. Blood samples were taken at rest and at isotime or immediately after exercise. Duration of control and NIV-supported exercise was similar, both 12.9 ± 2.8 min. Interleukin- 6 (IL-6) plasma levels increased significantly by 25 ± 9% in response to control exercise, but not in response to NIV-supported exercise. Leukocyte concentrations increased similarly after control and NIV-supported exercise by ∼15%. Plasma concentrations of C-reactive protein, carbonylated proteins, and production of reactive oxygen species by blood cells were not affected by both exercise modes. This study demonstrates that NIV abolishes the IL-6 response to exercise in muscle-wasted patients with COPD. These data suggest that the respiratory muscles contribute to exercise-induced IL-6 release in these patients.

Chronic obstructive pulmonary disease (COPD) is characterized by irreversible airflow limitation (Celli & Macnee, 2004). Yet, increasing evidence indicates that COPD also includes severe systemic manifestations, like skeletal muscle dysfunction and cardiovascular impairments (Sidney et al., 2005). Many of the systemic consequences of COPD have been related to the presence of systemic inflammation (Agusti, 2007). While the degree of systemic inflammation in COPD patients at rest has been marked as low grade, several studies have demonstrated that exercise aggravates the level of systemic inflammatory mediators (Rabinovich et al., 2003; van Helvoort et al., 2005; Mercken et al., 2009a). The systemic inflammatory response to exercise in COPD patients even occurs after submaximal exercise, like a 6-min walk test (van Helvoort et al., 2007).

Considering the important role of systemic inflammation in the pathogenesis of COPD, it seems therapeutically attractive to attenuate the inflammatory response to exercise. Although the exact origin of the inflammatory response is currently unclear, a potential role has been ascribed to the respiratory muscles (Vassilakopoulos et al., 2004). During exercise, the respiratory muscles of patients with COPD are excessively loaded (Evison & Cherniack, 1968). Increased loading of the respiratory muscles, even in the absence of total body exercise, leads to a systemic inflammatory response (Vassilakopoulos et al., 2004). Therefore, we aimed to investigate whether unloading of the respiratory muscles could attenuate the inflammatory response to exercise in patients with COPD.

Non-invasive ventilation (NIV) is a commonly used intervention to unload the respiratory muscles (Polkey et al., 1996; van ‘t Hul et al., 2002; Borghi-Silva et al., 2008). Several studies have shown that NIV can improve exercise tolerance in COPD patients (van ‘t Hul et al., 2002; van ‘t Hul et al. 2004). Yet, the effect of NIV on the inflammatory response to exercise has never been studied. Therefore, we designed a pilot study that investigated whether the inflammatory response to exercise in patients with COPD could be suppressed by the appliance of NIV. We aimed the outcomes of the current study to be of potential clinical use during, for example, pulmonary rehabilitation and activities of daily life. Accordingly, we chose to investigate the inflammatory response to an exercise intensity comparable with daily life activities and to adjust NIV settings non-invasively and practically applicable, i.e., according to patients comfort.

Materials and methods

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. Perspective
  7. Acknowledgements
  8. Funding
  9. References

Subjects

Because the inflammatory response to exercise is known to be more pronounced in COPD patients with low fat-free mass than in patients with normal fat-free mass (van Helvoort et al., 2006b), the current study included COPD patients with low fat-free mass to study the effect of NIV [fat-free mass index <16 kg/m2 for men and <15 kg/m2 for women (Schols et al., 1993) ]. Eight stable COPD patients were recruited from our outpatient clinic. Exclusion criteria were current smoking, other systemic inflammatory diseases, exercise-limiting comorbidity, long-term oxygen therapy, use of oral corticosteroids, an exacerbation within 6 weeks before the study, or the absence of ventilatory limitation (2003) during control exercise at 40 W. Because antioxidant supplementation may affect the inflammatory response to exercise (Vassilakopoulos et al., 2003), the use of N-acetylcystein (in two patients) and supplemental vitamins (in three patients) was discontinued at least 1 week before start of testing. The study was conducted according to the Declaration of Helsinki and was approved by the medical ethical committee of our hospital. Written informed consent was obtained from all participants.

Study design

As part of the characterization procedure, pulmonary function testing (Masterlab, Viasys Healthcare, Hoechberg, Germany) was performed (Miller et al., 2005), with reference values according to (Quanjer et al., 1993). Fat-free mass index was assessed by a single-frequency bioelectrical impedance analysis (Biostat 1500, Bodystat LTD, Douglas, Isle of Man, British Isles).

In two subsequent visits, the systemic responses to exercise with NIV compared with control were evaluated in a cross-over design. Because we anticipated that patients would exercise longer when receiving NIV support and we wanted to compare blood samples taken at isotime, we chose that patients exercised without NIV at their first visit and with NIV at their second visit. At both visits, patients performed constant work-rate cycle exercise until symptom limitation, or for maximally 20 min. In order to simulate daily life activities and to standardize the exercise, ergometry was performed at 40 W (van Helvoort et al., 2006a), which corresponds to ∼3–4 metabolic equivalents comparable with the energy expenditure during walking (Ainsworth et al., 2011). Heart rate was measured continuously by electrocardiography. An arterial cannula was inserted into the brachial artery under local anesthesia at each visit. Arterial blood samples were drawn at rest and immediately after exercise (max) for determination of blood gases and markers of systemic inflammation and oxidative stress. Arterial blood gases and lactate levels were analyzed immediately after sampling using Bayer Rapidlab 865 blood gas analyzer (Bayer, Leverkusen, Germany). Measurements after exercise were corrected for plasma volume shifts according to Dill and Costill (1974). In addition, patients scored their breathlessness and leg discomfort on a 10-point Borg scale at rest and at max.

During the first visit (control visit), minute ventilation was measured using Oxycon Pro (Viasys Healthcare, Hoechberg, Germany). Mean minute ventilation during control exercise was 90 ± 10% of predicted maximal ventilation [=37.5 × forced expiratory volume in 1 s (FEV1) (ATS/ACCP, 2003) ]. At the end of the first visit, NIV (VPAP III, Resmed, Bella Vista, Australia; bi-level positive airway pressure modus) with a tight-fitting partial face mask was introduced in order for the patients to be familiarized with it for the second visit. Accordingly, inspiratory positive airway pressure (IPAP) and expiratory positive airway pressure (EPAP) were adjusted on the basis of patient comfort at rest (Vitacca et al., 2000). The mean level of IPAP was 12.0 ± 0.8 cmH2O (range 10–14 cmH2O) and the mean EPAP was 5.0 ± 0.4 cmH2O (range 4–6 cmH2O). At the second visit, NIV was applied during the 40-W constant work-rate exercise testing. The rest blood sample was taken before starting NIV. The max blood sample was drawn immediately after exercise or at isotime when patients exercised longer than during control exercise to exclude an effect of exercise time. The second visit occurred within 2 weeks after the first visit. Because constant work-rate cycle test–retests have been shown to be highly reproducible in patients with COPD (van ‘t Hul et al., 2003), we anticipated that exercise capacities at the two visits were comparable. All measurements were performed by a trained investigator.

Markers of systemic inflammation and oxidative stress

Quantitative determination of interleukin (IL)-6 was performed using high sensitivity enzyme-linked immunosorbent assay (ELISA) in kit form (Quantikine® HS, R&D Systems, Minneapolis, MN, USA). Leukocyte and neutrophil count were determined according to standardized clinical laboratory assays. High-sensitivity C-reactive protein levels were determined by nephelometry (Siemens Dade Behring, Deerfield, IL, USA).

Production of reactive oxygen species (ROS) by whole blood in response to stimulation with phorbol myristate acetate was evaluated by luminol-enhanced chemiluminescence measured in an automated luminometer (Microplate Luminometer LB 96V, EG&G Berthold, Vilvoorde, Belgium), as described previously (Versleijen et al., 2008). The peak oxygen radical production [relative light units (RLUs) ] was calculated. Levels of protein carbonyls, a marker of protein oxidation, were measured by means of ELISA as described previously (Zusterzeel et al., 2000).

Statistics

Data are presented as mean ± standard deviations. To establish that patients’ conditions were comparable before both exercise conditions, paired Wilcoxon signed rank test was performed on values at rest. The responses to exercise, for each exercise mode, were also evaluated by paired Wilcoxon signed rank test. Two-way repeated measures (doubly multivariate repeated measures) were performed to test whether an interaction-effect between exercise and intervention existed, i.e., a difference in the responses to control exercise and NIV-supported exercise. A P-value less than 0.05 was considered statistically significant. Data were analyzed with the Statistical Package for the Social Sciences (SPSS), version 16.0 (SPSS Inc, Chicago, IL, USA).

Results

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. Perspective
  7. Acknowledgements
  8. Funding
  9. References

Subjects

Table 1 shows baseline anthropometric and pulmonary function data of the eight included muscle-wasted COPD patients. Mean FEV1 was 42% of predicted values, and ranged from 18% to 68%, indicating moderate to very severe airflow obstruction. Furthermore, the study group showed hyperinflation and reduced lung diffusion capacity.

Table 1. Patient characteristics
  1. Data are presented as mean ± standard deviation.

  2. BMI, body mass index; DLCO, diffusing capacity for carbon monoxide; FEV1, forced expiratory volume in 1 s; FFMI, fat-free mass index; FRC, functional residual capacity; FVC, forced vital capacity; RV, residual volume; TLC, total lung capacity; Pimax, maximal inspiratory mouth pressure.

N 8
Gender (M/F)4/4
Age (years)62 ± 2
BMI (kg/m2)23.1 ± 2.6
FFMI (kg/m2) (M/F)14.7 ± 1.7/14.7 ± 0.5
Pulmonary function 
FEV1 (L)1.12 ± 0.40
FEV1 (%pred)42 ± 17
FVC (L)3.41 ± 0.40
FVC (%pred)101 ± 18
FEV1/FVC (%)33 ± 12
FRC (%pred)142 ± 34
RV (%pred)144 ± 35
TLC (%pred)117 ± 17
DLCO (%pred)45 ± 13
Pimax (%pred)102 ± 27

Physiological responses

Mean duration of control exercise and exercise with NIV was similar, both 12.9 ± 2.8 min. Baseline physiological values were not significantly different between both exercise conditions. Table 2 shows the physiological responses to both modes of exercise. Heart rate increased during exercise (P < 0.05), but did not reach maximal predicted values. The heart rate responses to the different exercise modes were comparable. Although patients did not become hypoxemic during exercise, arterial oxygen pressures reduced in response to both exercise modes. The decrease in arterial oxygen pressure was more after exercise with NIV support than after control exercise (P < 0.05). Arterial carbon dioxide pressures increased significantly during both control and NIV-supported exercise without a significant difference between the two exercise modes. Blood lactate levels, as well as sensations of dyspnea and leg discomfort increased significantly after both exercise modes without any differences between the two exercise modes.

Table 2. Physiological responses of control and NIV-supported cycle tests
 ControlNIV
Pre-exerciseResponse to exercise (Δ)Pre-exerciseResponse to exercise (Δ)
  1. Data are presented as mean ± standard deviation.

  2. a

    Exercise effect P < 0.05.

  3. b

    Response is different than upon control exercise P < 0.05.

  4. Δ, max-rest; NIV, non-invasive ventilation; PaCO2, arterial carbon dioxide tension; PaO2, arterial oxygen tension.

Heart rate (beats/min)78 ± 13+41 ± 12a 74 ± 6+41 ± 18a
PaO2 (kPa)9.6 ± 1.5−0.5 ± 1.010.0 ± 1.4−1.2 ± 1.0a, b
PaCO2 (kPa)5.1 ± 0.5+0.5 ± 0.4a 5.2 ± 0.4+0.9 ± 0.2a
Lactate (mmol/L)1.3 ± 0.5+2.2 ± 1.8a 1.1 ± 0.4+2.2 ± 1.4a
Dyspnea (Borg units)0.9 ± 1.0+3.6 ± 2.3a 1.0 ± 1.1+4.8 ± 3.4a
Leg discomfort (Borg units)0.4 ± 0.7+2.9 ± 2.7a 0.6 ± 2.2+1.6 ± 2.0a

Systemic inflammatory and oxidative stress responses

Absolute values at rest and the responses to both exercise modes are presented in Tables 3 and 4. Baseline values of systemic inflammation and oxidative stress were not significantly different between both pre-exercise states.

Table 3. Systemic inflammatory response to control and NIV-supported exercise
 ControlNIV
Pre-exerciseResponse to exercise (Δ)Pre-exerciseResponse to exercise (Δ)
  1. Data are presented as mean ± standard deviation.

  2. a

    Exercise effect P < 0.05.

  3. b

    Response is different than upon control exercise P < 0.05.

  4. CRP, C-reactive protein; Δ, max-rest; NIV, non-invasive ventilation.

IL-6 (pg/mL)2.7 ± 2.1+0.4 ± 0.3a 2.8 ± 2.3+0.0 ± 0.6b
Leukocytes (109/L)7.8 ± 2.1+0.8 ± 1.0a 6.9 ± 1.5+1.2 ± 0.8a
Neutrophils (109/L)5.2 ± 1.6+0.5 ± 0.5a 4.4 ± 0.8+0.6 ± 0.3a
CRP (mg/L)4.8 ± 5.5+0.0 ± 0.12.8 ± 2.6−0.1 ± 0.2
Table 4. Oxidative stress response to control and NIV-supported exercise
 ControlNIV
Pre-exerciseResponse to exercise (Δ)Pre-exerciseResponse to exercise (Δ)
  1. Data are presented as mean ± standard deviation.

  2. Δ, max-rest; NIV, non-invasive ventilation; RLU, relative light units; ROS, reactive oxygen species.

ROS (RLU/s)230 ± 123−6.6 ± 40.5185 ± 59+22.6 ± 14.8a
Protein carbonyls (nM)6099 ± 4856+1956 ± 39215058 ± 3679+274 ± 1182

IL-6 plasma levels increased significantly in response to control exercise, while IL-6 levels did not rise significantly upon exercise supported with NIV (Table 3). Accordingly, the IL-6 response to NIV-supported exercise was significantly different from the response to control exercise (i.e., an interaction-effect, P < 0.05). The different response to control exercise and NIV-supported exercise is also illustrated by Fig. 1, in which IL-6 plasma levels upon exercise are expressed as relative changes from rest. IL-6 plasma levels increased by ∼25% upon control exercise, while IL-6 plasma levels after NIV-supported exercise were only ∼9% higher than at rest. Leukocyte plasma concentrations after control and NIV-supported exercise were significantly higher than at rest (Table 3). The leukocyte response to NIV-supported exercise was not significantly different from the response to control exercise. Likewise, neutrophil plasma levels also increased significantly and similarly in response to both exercise conditions (Table 3). Neither control exercise nor NIV-supported exercise affected the plasma levels of CRP (Table 3).

figure

Figure 1. The relative responses from rest of interleukin-6 (IL-6) plasma levels to control and non-invasive ventilation (NIV)-supported exercise. # P < 0.05.

Download figure to PowerPoint

The capacity of whole blood to produce ROS, a marker of oxidant production, was unaffected by control exercise, but increased significantly upon exercise with NIV support (Table 4). The plasma levels of carbonylated proteins, a footprint of oxidative stress, were neither affected by control exercise nor by NIV-supported exercise (Table 4).

Discussion

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. Perspective
  7. Acknowledgements
  8. Funding
  9. References

The main finding of the current pilot study is that NIV support abolishes the IL-6 response to exercise in muscle-wasted patients with COPD. Yet, while NIV support prevents IL-6 levels to rise, plasma leukocyte and neutrophil concentrations still increase upon exercise. So, NIV support during exercise in these patients is not associated with a complete attenuation of the inflammatory response to exercise. Because NIV is known to specifically unload the respiratory muscles, the results from the present pilot study provide new hypotheses on the mechanisms of the IL-6 response to exercise in COPD. Furthermore, as NIV-supported exercise is increasingly being applied in research as well as rehabilitation settings, the current findings may be relevant to consider when assessing clinical outcomes of NIV during exercise.

Systemic inflammatory and oxidative stress responses

The systemic inflammatory response to exercise has been extensively investigated, both in health and disease. The most pronounced marker of this response is IL-6 (Febbraio & Pedersen, 2002). Compared with healthy individuals, the IL-6 response to exercise is higher in patients with COPD, particularly after exercise of submaximal intensity (van Helvoort et al., 2006b). In keeping with previous data, the current study shows that exercise at 40 W engenders a significant rise of plasma IL-6 levels in COPD patients with low fat-free mass. Because investigations in healthy subjects made clear that contracting skeletal muscle is the main source of circulating IL-6 in response to exercise (Pedersen & Hoffman-Goetz, 2000), IL-6 is frequently referred to as a myokine. Interestingly, the amount of IL-6 released from muscles seems to depend on exercise intensity (Helge et al., 2003). However, in that respect, it seems paradoxical, that COPD patients show a higher IL-6 response at much lower workloads compared with healthy subjects (van Helvoort et al., 2006b). Findings from the current study provide a potential explanation for this apparent contradiction. The load on the peripheral muscles was identical between the two exercise side modes, i.e., 40 W, while the IL-6 response to exercise was almost completely abolished after exercise with NIV support. So the elevated IL-6 plasma levels upon exercise in COPD patients are not related to the load on the peripheral muscles. However, although we did not measure the load on the respiratory muscles in this pilot study, we expect to have unloaded the respiratory muscles by applying NIV. Accordingly, these data suggest that the main cause of an exaggerated IL-6-response in COPD patients during exercise is not the load on the peripheral muscles, but the load on the respiratory muscles. This postulation is supported by several previous observations. For example, Vassilakopoulos et al. demonstrated that increasing the load on the inspiratory muscles in healthy individuals leads to elevated IL-6 concentrations in plasma (Vassilakopoulos et al., 1999). Moreover, the load on the respiratory muscles during exercise is excessively increased in COPD patients compared with healthy subjects (Evison & Cherniack, 1968). Furthermore, Mercken and coworkers showed that localized leg muscle exercise of COPD patients did not result in elevated plasma IL-6 levels (Mercken et al., 2009b), suggesting that the respiratory muscles rather than the peripheral muscles produce IL-6 during whole body exercise. Indeed, in animals, it has been demonstrated that cytokine expression in the diaphragm is upregulated in response to loaded breathing (Sigala et al., 2011). An alternative explanation might be that the peripheral muscles start to produce IL-6 because of local vasoconstriction induced by increased load on the respiratory muscles, also known as the respiratory muscle metaboreflex (Harms et al., 1997; Dempsey et al., 2006). So, the present findings and previous studies provide evidence that increased loading of the respiratory muscles induces the supranormal IL-6 response to exercise observed in COPD patients. The exact origin of IL-6, either the peripheral or respiratory muscles, could be an interesting topic for future studies following up on the present pilot study.

In contrast to IL-6, NIV support could not prevent the rise of leukocytes and neutrophils in response to exercise. The extra amounts of circulating leukocytes that appear upon exercise probably arise from an increased blood flow through lymphoid tissue, the non-circulatory leukocyte pool. Increased heart rate and vasomotor tone as a response to stress hormones during exercise are thought to lead to the release of extra leukocytes into the circulation (Hoffman-Goetz & Pedersen, 1994). In the current study, we did not measure the effect of NIV on, for example, catecholamines, but we did show that NIV had no effect on the heart rate response to exercise. This could explain why the increase of leukocyte concentrations was not affected by NIV support. Although the main objective of the current study was to investigate the effect of NIV on markers of systemic inflammation, we additionally examined some markers of oxidative stress because oxidative stress and systemic inflammation have often been linked (Vassilakopoulos et al., 2003). For example, it is well known that leukocytes and in particular neutrophils are able to produce ROS under conditions of stress (Suzuki et al., 1996). As ROS modify the structure and function of proteins, fatty acids, and genetic material, their presence in the circulation has been proposed to be harmful. In our study, we found no effect of control exercise on the capacity of blood samples to produce ROS. In line with that, the plasma levels of carbonylated proteins, a footprint of oxidative protein damage, were not elevated upon control exercise. This is in contrast with previous studies from our lab, which did show an oxidative stress response to exercise in muscle-wasted COPD patients (van Helvoort et al., 2006a; van Helvoort et al. 2007). The discrepancy between the current study and those previous studies can probably be explained by less loss of fat-free mass in the patients that were currently studied, because indeed we previously demonstrated that the magnitude of the oxidative stress response is closely related to the severity of fat-free mass loss (van Helvoort et al., 2007). A causative role for oxidative stress in inducing the IL-6 response to exercise in COPD patients has previously been proposed (van Helvoort et al., 2006a; Jammes et al., 2008). The present study does not support that concept. First, IL-6 levels elevated upon control exercise, without increased presence of carbonylated proteins. Moreover, the abolished IL-6 response to exercise with NIV support was accompanied by lower arterial oxygen pressures and increased capacity of blood cells to produce ROS. So, the release of IL-6 upon exercise can be inhibited despite plasma states that favor oxidative stress. The present findings therefore do not support the concept that IL-6 response to exercise is caused by increased systemic oxidative stress but rather point to an important role for excessive loading of the respiratory muscles. Of note, we do not exclude the involvement of oxidative stress signaling within the respiratory muscles. Vassilakopoulos et al. have previously shown that increased loading of the respiratory muscles induces oxidative stress and administration of anti-oxidants can downregulate the expression and release of cytokines by the diaphragm (Vassilakopoulos et al., 2002).

Clinical implications

The current finding that NIV support during exercise of COPD patients abolishes the IL-6 response, may have clinical implications. For example, high IL-6 levels in patients with COPD are often related to detrimental systemic effects, such as skeletal muscle weakness (Yende et al., 2006), insulin resistance (Bolton et al., 2007), exacerbations (Wedzicha et al., 2000), and the development of comorbidities (Sin & Man, 2006). Although a cause–effect relation of IL-6 and these systemic manifestations has never been determined in humans, it is noteworthy to mention that IL-6 overexpression and IL-6 infusion in rodents leads to airway inflammation (Kuhn III et al., 2000), skeletal muscle wasting (De et al., 2002; van Hees et al., 2011) and myocardial failure (Janssen et al., 2005). Therefore, it appears that depression of high IL-6 levels in patients with COPD is an attractive treatment. On the other hand, however, several recent studies point to a functional role for IL-6 in response to exercise. For example, IL-6 facilitates glucose metabolism during exercise (Helge et al., 2003). Furthermore, IL-6 may induce an anti-inflammatory environment following exercise by inhibiting the expression of the pro-inflammatory cytokine tumor necrosis factor-α and by stimulating the production of anti-inflammatory cytokines, such as IL-1 receptor antagonist and IL-10 (Pedersen & Fischer, 2007). Therefore, we do not exclude that the depressed IL-6 response during NIV-supported exercise may affect glucose metabolism and favor the presence of an inflammatory environment. So, considering the complex physiological function of IL-6, it is obvious that intervention with NIV during exercise in COPD could have important clinical implications. Yet, whether these implications are favorable or harmful to the condition of the COPD patient is currently unclear and needs to be addressed in future studies.

Study limitations

We acknowledge that the set-up of the current pilot study partially limits the interpretation of our data. First, although NIV is generally being applied to unload the respiratory muscles, we did not establish whether the load on the respiratory muscles was indeed reduced. As we wanted to resemble the clinical setting, we chose to adjust NIV support according to the patient's comfort and not by an invasive evaluation of lung mechanics and respiratory muscle function. Nevertheless, similar approaches have been used in previous studies and showed to be effective in unloading the respiratory muscles (Vitacca et al., 2000; Hussain et al., 2011). Therefore, we presume that NIV generally reduced the load on the respiratory muscles in the current study, but we also recognize that the NIV settings might not have been optimal for each patient. Remarkably, compared with control exercise, arterial oxygen pressure decreased more in response to NIV-supported exercise and arterial carbon dioxide pressures tended to increase more, suggesting that NIV reduced alveolar ventilation. Indeed, recent data from Hussain et al. show that NIV attenuated the increase in minute ventilation upon exercise while unloading the respiratory muscles in COPD patients at the same time (Hussain et al., 2011). So, it could be that the appliance of NIV reduced alveolar ventilation in some of our patients, while unloading the respiratory muscles at the same time. This would explain the unexpected finding that patients did not exercise longer when supported by NIV. Despite all that, the fact that NIV appliance during exercise affects the IL-6 response in COPD patients still holds true. A second limitation of the study is that the present findings concern COPD patients with a low fat-free mass. As previous findings from our group have shown that the inflammatory response to exercise is more aggravated in muscle-wasted COPD patients than in non-muscle–wasted COPD patients (van Helvoort et al., 2006b), the current data cannot be easily extrapolated to COPD patients with normal fat-free mass. To that end, it is clinically important that future studies should address whether our findings also account for other subgroups of COPD.

Perspective

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. Perspective
  7. Acknowledgements
  8. Funding
  9. References

Increasing evidence show that systemic inflammation strongly contributes to the development of comorbidities in patients with COPD (Agusti, 2007). Previous studies from our group and others have demonstrated that the level of systemic inflammation is even aggravated as an acute response to exercise of these patients (van Helvoort et al., 2005; Mercken et al., 2009a). The present study demonstrates that respiratory muscle unloading can abolish the IL-6 response to exercise in COPD patients with low fat-free mass. This suggests that increased loading of the respiratory muscles contributes to an exaggerated exercise-induced IL-6 response in these patients. The present findings are of clinical relevance, as these were obtained under experimental conditions that fairly resemble clinical settings, i.e., the exercise intensity was moderate and NIV support was given according to patients comfort. Because NIV is increasingly being applied in scientific and clinical settings, and IL-6 plays an important role in the development of comorbidities in COPD (Sin & Man, 2006) as well as in the normal physiological response to acute exercise (Helge et al., 2003), it is important that follow-up studies address whether the effect of NIV on exercise-induced IL-6 response depends on (a) NIV settings; (b) exercise level; and (c) COPD-phenotype.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. Perspective
  7. Acknowledgements
  8. Funding
  9. References

The authors wish to acknowledge Ivo Derks and Ferdi Akankan from the Department of Pulmonary Function Testing for their help with the cycle tests; Marianne Linkels from the Department of Pulmonary Diseases for performing the IL-6 measurements; and Wilbert Peters and Hennie Schaap-Roelofs from the Department of Gastroenterology and Hepatology for their laboratory assistance.

Funding

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. Perspective
  7. Acknowledgements
  8. Funding
  9. References

This study has been supported by an unrestricted educational grant from AstraZeneca.

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  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. Perspective
  7. Acknowledgements
  8. Funding
  9. References
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