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doi:10.1378/chest.06-1655
(Chest. 2007; 131:439-445)
© 2007 American College of Chest Physicians
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Six-Minute Walking-Induced Systemic Inflammation and Oxidative Stress in Muscle-Wasted COPD Patients*

Hanneke A. C. van Helvoort, MSc; Yvonne F. Heijdra, MD, PhD; Roline C. C. de Boer, MSc; Astrid Swinkels, MSc; Hub M. H. Thijs, MSc and P. N. Richard Dekhuijzen, MD, PhD

* From the Department of Pulmonary Diseases, Institute for Fundamental and Clinical Human Movement Sciences, Radboud University Nijmegen Medical Centre, the Netherlands.

Correspondence to: Hanneke A.C. van Helvoort, MSc, Radboud University Nijmegen Medical Centre, Department of Pulmonary Diseases (454), PO Box 9101, 6500 HB Nijmegen, the Netherlands; e-mail: H.vanHelvoort{at}long.umcn.nl

Abstract

Background: Systemic inflammation and oxidative stress are potential mechanisms for muscle wasting in COPD patients. Six-minute walking testing (6MWT) has been suggested as simple and valid exercise test in COPD that is well tolerated, and reflective of activities of daily living. The present study investigated physiologic and systemic immunologic responses to a 6MWT in muscle-wasted patients with COPD and compared them with maximal cardiopulmonary exercise testing (CPET).

Methods: Ten patients with muscle-wasted COPD were included (fat-free mass index [FFMI]: men, < 16 kg/m2; women, < 15 kg/m2). 6MWT and CPET were performed in random order. The physiologic response was followed by a mobile oxycon. Arterial blood was obtained at rest and after exercise to measure blood gases and markers of systemic inflammation and oxidative stress.

Results: In these patients (FEV1 55 ± 4% of predicted [mean ± SE]), the 6MWT was a submaximal, albeit intense, exercise as reflected by oxygen uptake (VO2), minute ventilation, heart rate, and lactate values. Leukocytosis was less intense after 6MWT compared to CPET. Contrary, the increase in interleukin-6, free radical release by neutrophils, oxidation of proteins and lipids, and the reduction in antioxidant capacity were similar after both exercises. FFMI was inversely related to 6MWT-induced increases in protein and lipid peroxidation.

Conclusions: This study shows that a 6MWT induces a systemic immunologic response in muscle-wasted patients with COPD, which is comparable to CPET-induced responses. The correlation between systemic oxidative stress and the degree of muscle wasting supports a possible causal relation between systemic inflammation, oxidative stress, and muscle wasting.

Key Words: cardiopulmonary exercise test • COPD • oxidative stress • physiology • 6-min walking test • systemic inflammation

COPD is defined currently by the American Thoracic Society (ATS)/European Respiratory Society as a disease characterized by airflow limitation that is not fully reversible and produces significant systemic consequences.1 This systemic involvement in COPD has become extremely important since it seems conceivable that exploring the presence of systemic biomarkers and their relation to systemic manifestation of the disease will help us in developing and applying novel strategies that will improve outcome of our patients. Based on the current understanding of the pathobiology of COPD, most notably suggested markers are the inflammatory cells and their products that are believed to be the proximate causes of tissue destruction in patients with COPD.2 The exact meaning of these biomarkers are not elucidated yet, and may be multifactorial, but both systemic inflammation and oxidative stress have been associated with loss of muscle mass and muscle dysfunction.3456 Very recently, moderate and high-intensity cycle ergometry has shown to increase systemic inflammation and oxidative stress,7 especially in the subgroup of COPD patients with muscle wasting.5 Although strong evidence is lacking, frequent exposure to these effects might play a role in the ongoing muscle wasting and its consequences in these patients. Additionally, it was shown that cycling-induced systemic inflammation in patients with muscle wasting could be attenuated and oxidative stress be prevented by supplemental oxygen during exercise.8 Based on these results, we postulated that daily life activities, which can be classified as moderate intense for these patients, can cause frequent bursts of systemic inflammation and oxidative stress that may be involved in muscle wasting. Patients with COPD, however, are relatively inactive, and they will not perform cycle exercises regularly. The 6-min walking test (6MWT) has been suggested as a simple and valid exercise test in COPD, which is well tolerated, and reflective of activities of daily living.9 The physiologic responses to 6MWT in patients with COPD has been studied previously and described as maximal10 or submaximal11 sustainable exercise in these patients. The current study was designed to characterize both the physiologic and systemic immunologic responses to a 6MWT in muscle-wasted patients with COPD and compare them with the responses to maximal cardiopulmonary exercises testing (CPET).

Materials and Methods

Subjects
The study group included 10 ex-smoking patients with muscle-wasted COPD (6 men; fat-free mass index [FFMI]: men, < 16 kg/m2; women, < 15 kg/m2).12 The patients were recruited from our outpatient clinic and had moderate-to-severe COPD according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification.1 All had been free of exacerbations for at least 2 months prior to the study, and had stopped smoking at least 6 months before inclusion. Exclusion criteria were the use of oral corticosteroids, long-term oxygen therapy, and other chronic inflammatory or exercise-limiting diseases. The use of inhaled corticosteroids (n = 6) and antioxidants (N-acetylcysteine, n = 3) was discontinued 1 week prior to exercise testing. All patients were receiving bronchodilator therapy, and none used theophylline. 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 subjects.

Study Design
As part of the characterization procedures, resting pulmonary function, bioelectrical impedance analysis (Biostat 1500; Bodystat Ltd; Douglas, Isle of Man, UK), and peripheral muscle strength, as described by van Helvoort et al,5 were performed in all patients. Weight parameters were adjusted for body surface to give body mass index (BMI) and FFMI. On 2 different study days (separated by 1 week), two exercise protocols were performed in random order: 6MWT and CPET. During both exercises, the physiologic response was followed in all participants. In all patients, arterial blood was obtained from a catheter in the radial artery to measure blood gases, lactate concentrations, and systemic inflammation and oxidative stress at rest and in response to the exercises.

Exercise Testing
A portable breath-by-breath system (Mijnhardt/Jaeger; Bunnik, the Netherlands), a pulse oximeter (Datex; Helsinki, Finland), and a polar belt were used to monitor oxygen uptake (VO2), carbon dioxide production (VCO2), respiratory exchange ratio, minute ventilation (VE), and heart rate (HR) on-line during exercise. Validation of this new system, the mobile oxycon, can be found in as on-line Supplementary material. Before exercise, a catheter was inserted into the radial artery to obtain arterial blood before, during and directly after (within 15 s) exercise.

The 6MWT was performed according to the ATS guidelines.13 All patients were familiar with the test. A straight walking course of 30 m was used, and two cones marked the turnaround points. Before the 6MWT, the patient sat in a chair for at least 30 min to measure stable physiologic and immunologic baseline values. After starting the exercise, participants were encouraged every minute with standardized phrases. Patients were allowed to stop and rest during the 6 min of exercise, but none of the participants in this study stopped walking before finishing the complete 6 min. A maximal, symptom-limited, incremental bicycle test was performed on an electrical braked cycle ergometer (Masterlab; Jaeger; Würzburg, Germany) according to the ATS guidelines.14

Analysis
Arterial blood gases (oxygen tension, PaO2, PaCO2) and lactate levels were determined immediately after sampling with a gas analyzer (model 860; Chiron; Norwood, MA). Systemic inflammation was characterized measuring the number of circulating leukocytes (standard laboratory tests), and plasma levels of interleukin (IL)-6 (R&D Systems; Minneapolis, MN) before and after the exercise. Oxidative response was evaluated by determination of production of reactive oxygen species (ROS) by isolated neutrophils (stimulated with phorbol myristate acetate [PMA]).1516 Total antioxidant capacity of plasma,17 plasma levels of carbonyls (protein oxidation),18 and plasma levels of thiobarbituric acid reactive substances (TBARs) [lipid peroxidation]19 were measured as described by others. Measurements after exercise were corrected for plasma volume shifts according to Dill and Costill.20 Detailed information about the measurements can be found as online supplementary material.

Statistical Analysis
Group data are expressed as mean values ± SE. Comparisons between rest and exercise values were made using Student paired t tests (or Wilcoxon signed-rank test if normal distribution was not assumed). When the response to exercise was expressed as percentage change compared to baseline, a one-sample t test (or Mann Whitney U test) was used. Comparisons between 6MWT and CPET were made using Student paired t tests (or Wilcoxon signed-rank test). One-way analyses of variance for repeated measurements were performed to examine physiologic profiles at the different exercise protocols. Spearman rank tests were used to evaluate the correlations between physiologic response, immune response, and muscle wasting. The level of statistical significance was set at p < 0.05.

Results

The study group (Table 1 ) showed moderate-to-severe airflow obstruction (FEV1, 1.55 ± 0.20 L; 55 ± 4% of predicted; range, 36 to 74% of predicted) without arterial hypoxemia or hypercapnia at rest. Mean FFMI was 14.1 kg/m2 in women and 14.8 kg/m2 in men.


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  		Table 1.. Subject Characteristics (n = 10)*

 
Physiologic Responses
Physiologic responses to 6MWT and CPET are compared in Table 2 . CPET resulted in significantly higher peak VO2 (p < 0.01) and VE (p < 0.01) than 6MWT. Also, HR and lactate values were significantly lower after 6MWT compared with CPET (p < 0.01 and p < 0.001, respectively). Detailed information on the physiologic responses is provided in the online supplement.


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  		Table 2.. Physiologic Responses to CPET and 6MWT*

 
Immunologic Responses
A significant leukocytosis occurred after both CPET (p < 0.001) and 6MWT (p < 0.01), which was caused by increases in all subsets. Compared to the response to CPET, the increase of the circulating inflammatory cells was less intense after the 6MWT (Fig 1 ), with significantly lower changes in total leukocytes (CPET, + 20%; 6MWT,+ 10%; p < 0.05) and lymphocytes (CPET, + 38%; 6MWT,+ 17%; p < 0.01).


Figure 1
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  		Figure 1.. Leukocytosis to exercise. Comparison of increases in leukocytes and subsets after CPET and 6MWT. *p < 0.05, **p < 0.01 6MWT vs CPET; ns = not significant.

 
Plasma levels of IL-6 were significantly increased after CPET (from 5.62 ± 1.1 to 6.33 ± 1.4 pg/mL, p < 0.05) and 6MWT (from 5.95 ± 1.3 to 6.77 ± 1.5 pg/mL, p < 0.05), as shown in Figure 2 . The mean increase after walking was not different from the response to CPET (0.82 ± 0.3 pg/mL vs 1.0 ± 0.4 pg/mL, p > 0.05).


Figure 2
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  		Figure 2.. IL-6 response to exercise. Both CPET and 6MWT induced a significant increase of IL-6 levels compared to rest values. The IL-6 response was comparable between the two different exercises. #p < 0.05 vs rest.

 
Exercise-induced free radical production by neutrophils (Fig 3 , top, A). Isolated neutrophils produced significantly more ROS after walking than at rest (change of 28 ± 8% in stimulated cells, p < 0.01). Comparable changes in neutrophil ROS production were observed after CPET (change of 29 ± 11%, p < 0.01). While the production of oxidants increased, plasma antioxidant capacity significantly decreased in response to exercise (Fig 3, bottom, B). A relatively small but consistent decrease of approximately 8% after 6MWT resembled the response to CPET. As markers of free radical-induced tissue or cell damage, both plasma levels of carbonyls and TBARs were significantly elevated after 6MWT (p < 0.05 and p < 0.01, respectively) [Fig 4 ]. Also after CPET, levels of TBARs were increased (p < 0.05), whereas carbonyls remained unchanged. Finally, the magnitude of the systemic oxidative stress response was related to the degree of muscle wasting. Figure 5 shows that increases in both plasma carbonyls and TBARs were significantly correlated to FFMI (r = 0.83, p < 0.01, and r = 0.75, p < 0.05, respectively). Contrary, systemic oxidative stress response was not correlated with BMI (p > 0.05).


Figure 3
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  		Figure 3.. Production of ROS by PMA-stimulated neutrophils (top, A), and plasma total antioxidant capacity (bottom, B) before and after CPET and 6MWT. Exercise-induced oxidative burst was comparable between cycling and walking. RLU/s = relative light units per second (chemiluminescence). Antioxidant responses were not different between the two exercises. #p < 0.05 vs rest, ##p < 0.01 vs rest.

 

Figure 4
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  		Figure 4.. Oxidative stress in response to CPET and 6MWT. Plasma levels of carbonyls (protein oxidation) [top, A] and TBARs (lipid peroxidation) [bottom, B] at rest and after CPET and 6MWT. #p < 0.05, ##p < 0.01 vs rest; see Figure 1 legend for expansion of abbreviation.

 

Figure 5
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  		Figure 5.. Relation between muscle wasting and magnitude of exercise-induced oxidative stress. FFMI was inversely correlated with 6MWT-induced increases in both plasma carbonyls (r = 0.83, p < 0.01) and TBARs (r = 0.75, p < 0.05).

 
Discussion

The most important finding of the current study in COPD patients with muscle wasting is the increased systemic inflammation and oxidative stress after 6MWT. Both the IL-6 and oxidative response to 6MWT are comparable to CPET-induced responses. Furthermore, the degree of muscle wasting was correlated with the increase of oxidative stress. Physiologically, the 6MWT is a submaximal, albeit intense, exercise in these patients, as reflected by lower VO2, VE, and lactate values after walking compared to CPET.

Physiologic Response
In contrast with findings of Troosters et al,10 who found identical VO2 and HR after 6MWT and CPET, the physiologic burden imposed on the system, in terms of ventilatory (VO2,VE) cardiovascular (HR) and metabolic response (lactate), was lower after 6MWT than at peak cycling in the present study. Disagreement between the studies may be due to differences in patient characteristics. Our patients showed slightly higher FEV1, less hyperinflation, and more muscle wasting compared to the patients in the study by Troosters et al.10 Furthermore, 6-min walking distance was considerably higher in the patients of Troosters et al,10 although maximal work rates during cycling were similar.

Systemic Immunologic Response
Despite the fact that the leukocytosis of exercise21 is affected by type, intensity, and duration of the exercise, several consistent patterns emerge regarding the leukocyte subpopulations in blood. The current study showed that a 6MWT already induces a typical systemic leukocytosis as a result of an increase in all leukocyte subpopulations. Immediately after start of muscular exercise, epinephrine and norepinephrine are released into the plasma. These stress hormones have marked physiologic effects on HR and vasomotor tone, and ultimately on blood flow through lymphoid tissues and leukocyte circulation patterns.22 Catecholamines increase almost linearly with the duration of exercise and exponentially with intensity, when it is expressed relative to the individual’s peak VO2.23 In line with the observation that the 6MWT is another type of exercise, less intense and a little shorter than CPET, the leukocytosis was less pronounced after 6MWT. In contrast, the plasma IL-6 response to exercise was similar between 6MWT and CPET. IL-6 precedes the appearance of other inflammatory mediators24 and is related to fat, protein, and muscle depletion.25 Inflammatory markers have indeed been found in skeletal muscles of patients with COPD.26 Whether IL-6 indeed plays a role in the ongoing and progressing systemic inflammation and its consequences in COPD needs to be elucidated further.

Regarding the oxidative response, earlier results have shown that exercise in COPD leads to a disturbance of the oxidant/antioxidant balance, which may result in free radical-mediated tissue damage.527282930 Following CPET and submaximal ergometry,56 the current data showed that the oxidative burst of neutrophils increased and total antioxidant capacity of plasma decreased after 6MWT, resulting in an increase of systemic oxidative stress. Although the 6MWT has been shown to be a submaximal, but relatively intense exercise for patients with COPD, it is also suggested to reflect activities of daily life.931 Consequently, this would support our concept that patients with COPD are regularly exposed to bursts of oxidative stress. In this respect, additional research to the exposure to oxidative stress and inflammation during daily activities is needed. Also, the question arises whether the described responses are specific for muscle-wasted patients with COPD and thereby support the concept of possible negative consequences, such as muscle wasting or damage. Previously, we showed that the systemic responses to high and moderate cycling indeed were specific for muscle-wasted patients with COPD and not seen in non–muscle-wasted patients and healthy subjects.5 Our present finding that the degree of muscle wasting was correlated with the magnitude of the systemic oxidative response further supports a possible causal relation between systemic inflammation, oxidative stress, and muscle wasting.

Some limitations of the present study and suggestions for future research deserve discussion. A relatively small number of patients was included in the study. The results, however, were very consistent within these 10 patients and thereby seem to be representative for these group of patients. Furthermore, muscle wasting is usually seen in GOLD stage 3 and 4 of the disease. Our study group had less severe COPD (GOLD 2 and 3). Diminished exercise capacity (maximal workload of 89 W) and clear respiratory and peripheral muscle weakness, however, supported the wasted condition in these patients with moderate-to-severe COPD.

Finally, attention should be paid to the clinical relevance of increased oxidative stress. Different mechanisms are known to be involved in the generation of free radicals, eg, mitochondrial electron transport chain, activated neutrophils, adenosine triphosphate degradation, aldehyde oxidase, arachidonic acid cyclooxygenase pathway, and nitric oxide synthase. Free radical release from contracting skeletal muscles have been shown, but using in vivo models it is impossible to exclude other sources, including liver, lung, small intestine, or circulating cells. There is good evidence that overproduction of free radicals is associated with muscle dysfunction. However, it is also known that free radicals are needed for optimal muscle function. To find out the clinical relevance of the oxidative burst, we support future research to markers of muscle damage and mechanistic studies to the source of oxidative stress and its consequences in these patients. Recently, it was shown that pulmonary rehabilitation was associated with reduced exercise-induced oxidative stress in COPD.30 However, patients with COPD showed a reduced ability to adapt to endurance training compared to healthy subjects, reflected in lower capacity to synthesize the antioxidative glutathione.32 This decreased glutathione synthesis may be of great concern in COPD patients with muscle wasting. Furthermore, supplemental oxygen has been show to attenuate exercise-induced free radical production by neutrophils and adenosine triphosphate degradation, resulting in the prevention of exercise-induced oxidative stress in patients with muscle-wasted COPD.8 Additionally, supplemental oxygen seemed to interfere in one of the inflammatory pathways, resulting in a decreased exercise-induced IL-6 response. Understanding the mechanisms of the systemic disease COPD will help us understanding the disease and finally optimize the treatment strategies for these patients.

In conclusion, the present study has shown that a 6MWT induces a systemic immunologic response in muscle-wasted patients with COPD, which is comparable to CPET-induced responses. Since walking is regularly performed during daily life, it might be postulated that muscle-wasted patients with COPD are regularly exposed to bursts of systemic inflammation and oxidative stress. The correlation between systemic oxidative stress and the degree of muscle wasting further supports a possible causal relation between systemic inflammation, oxidative stress and muscle wasting.

Footnotes

Abbreviations: ATS = American Thoracic Society; BMI = body mass index; CPET = cardiopulmonary exercise test; FFMI = fat-free mass index; GOLD = Global Initiative for Chronic Obstructive Lung Disease; HR = heart rate; IL = interleukin; ROS = reactive oxygen species; 6MWT = 6-min walking test; TBAR = thiobarbituric acid reactive substance; VCO2 = carbon dioxide production; VE = minute ventilation; VO2 = oxygen uptake

This study was financially supported by an unrestricted educational grant from AstraZeneca, the Netherlands.

The authors have no financial or other potential conflicts of interest to disclose.

Received for publication July 3, 2006. Accepted for publication September 13, 2006.

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