Systemic Immunological Response to Exercise in Patients with Chronic Obstructive Pulmonary Disease: What Does It Mean?van Helvoort H.A.C. · Heijdra Y.F. · Dekhuijzen P.N.R.
Department of Pulmonary Diseases and Institute for Fundamental and Clinical Human Movement Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Chronic obstructive pulmonary disease (COPD) is no longer seen as a pulmonary disease, but is increasingly associated with systemic effects with important clinical relevance. Systemic immunological changes in COPD patients are characterized by an increased number of circulating inflammatory cells, functional changes of the inflammatory cells, elevated plasma levels of cytokines, and oxidative stress. Physical exercise induces an abnormal systemic inflammatory and oxidative response in COPD patients, which is seen in both the circulation and the peripheral muscles. Although mechanisms and consequences of these effects are not yet fully understood, they could be harmful in COPD patients by inducing damage or functional changes in, for example, skeletal muscles. Whether these changes of the immune system can also affect the susceptibility to infections in these patients is unknown. The concept of COPD as a systemic rather than only a pulmonary disease also opens new perspectives on the development for new therapeutic interventions. The effects of new antioxidative and anti-inflammatory agents are investigated. A better understanding of the complexity of the systemic effects will aid the development of new therapies and management strategies for patients with COPD.
Copyright © 2006 S. Karger AG, Basel
‘Chronic obstructive pulmonary disease (COPD) is a disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases’ . This definition of COPD focuses exclusively on the lungs. Therefore, it is not surprising that in the diagnosis, staging, prognosis, and therapy of the disease mainly pulmonary variables are considered . Changes are introduced now, since recent studies have provided evidence that COPD is often associated with extrapulmonary abnormalities (table 1) . Systemic features of COPD are recognized as an important clinical feature of the disease and contribute significantly to decreased exercise capacity, decreased health status and increased mortality [2, 3]. For example, a multidimensional grading system was introduced recently to predict the risk of death among patients with COPD . Besides the forced expiratory volume in 1 s and the dyspnea score, this index also contains the 6-min walking test and the body mass index. For the first time, both pulmonary and systemic effects of COPD are integrated to stage the severity and estimate prognosis of the disease. Integration of both pulmonary and systemic effects and its consequences may contribute to a better understanding and management of the disease.
|Table 1. Systemic effects of COPD|
Exercise limitation, a common complaint in COPD patients  and a significant contributor to the poor quality of life [6, 7], has traditionally been explained by the increased work of breathing and dynamic hyperinflation that results from the airflow limitations in COPD patients [8, 9]. However, physical activity does not only affect the cardiovascular and respiratory system, but also has effects on the immune system and the skeletalmuscular system [10, 11]. The identification of systemic effects, like inflammation, oxidative stress and skeletal muscle wasting in COPD patients, has not only caused a shift in the view of the pathophysiology of COPD, but has also drawn attention to the role of exercise and rehabilitation in these patients . Until now, multiple studies have characterized the exercise-induced immune response in healthy subjects. However, regarding the immune response to exercise in COPD patients, a lot of information is still missing.
In this article, current knowledge regarding basal and exercise-induced systemic immunology, including inflammation and oxidative stress in patients with COPD, is reviewed and potential mechanisms and clinical consequences are discussed. Based on these data, targets for investigation of better clinical management of these patients are suggested.
Systemic Immunological Changes in COPD Patients
Intrapulmonary inflammation and oxidative stress play a key role in the pathogenesis of COPD. Increased numbers of neutrophils, macrophages and T lymphocytes as well as elevated concentrations of pro-inflammatory cytokines and oxidative stress are characteristic features within COPD . However, recent studies have shown that inflammation and oxidative stress are also present systemically (table 2). For example, increased numbers of circulating leukocytes were found in stable patients with COPD [14,15,16]. Furthermore, neutrophils harvested from the circulation of COPD patients showed enhanced chemotaxis and extracellular proteolysis . In another study, these cells produced more reactive oxygen species (the so called oxidative burst) compared with those from healthy subjects . Additionally, the expression of several surface adhesion molecules on neutrophils (for example CD11b), that play a role in the attraction and migration of cells, was higher in stable COPD patients than in healthy controls. Other abnormalities described in circulating neutrophils in COPD patients include the downregulation of a G protein subunit (stimulatory Gα) that is indirectly involved in the expression of adhesion molecules and the oxidative burst .
|Table 2. Low-grade systemic inflammation and oxidative stress in patients with COPD|
Little is known about the function of circulating lymphocytes in patients with COPD. Sauleda et al.  showed that the activity of cytochrome oxidase, the terminal enzyme in the mitochondrial electron transport chain, was increased in circulating lymphocytes from stable COPD patients compared with healthy non-smoking controls. This abnormality was also detected in other chronic inflammatory diseases , suggesting that it may be a non-specific marker of lymphocyte activation. Further, a higher percentage of CD8+ lymphocytes was found in COPD patients  compared with healthy subjects. Additionally, a lower CD4+/CD8+ ratio was associated with a decreased pulmonary function. The implication of these findings remains unclear. Because the CD4+/CD8+ ratio is genetically controlled in humans, it could be hypothesized that a smoker with a low CD4+/CD8+ ratio may be more susceptible for the development of COPD.
Next to inflammatory cells, numerous studies have reported increased levels of circulating cytokines and acute-phase proteins in the peripheral circulation of patients with COPD [22,23,24,25,26]. Abnormalities include increased concentrations of tumor necrosis factor (TNF)-α, its receptors (TNFR-55 and TNFR-75), interleukin (IL)-6, IL-8, and Fas and Fas ligand, as well as elevated levels of the acute-phase proteins C-reactive protein and lipopolysaccharide-binding protein. These increases were seen in clinically stable patients, but were generally more pronounced during exacerbations of the disease.
Besides inflammation, oxidative stress also plays an important role in the pathogenesis of COPD . Increased production of reactive oxygen species (by neutrophils) or insufficient antioxidant capacity leads to a disbalance between oxidants and antioxidants. An excessive amount of reactive oxygen species may be harmful to tissues by inducing functional or structural alterations . Different investigations have shown that markers of oxidative stress (antioxidant capacity, lipid peroxidation, and peroxidation of arachidonic acid) are increased in patients with COPD and even more pronounced during exacerbations [12, 28, 29]. Higher levels of oxidative stress found in smokers with a normal pulmonary function suggest that tobacco smoke plays a role in disturbing the balance between oxidants and antioxidants.
The mechanisms of the above-mentioned systemic immunological changes in COPD patients are unclear, but several mechanisms could be operative [for a review, see ref. . Firstly, tobacco smoke can cause endothelial damage and dysfunction of the systemic vessels [30, 31], as well as systemic oxidative stress . A second potential mechanism is that the pulmonary inflammatory process in the lung in COPD patients is the source of the systemic inflammation. Cytokines and oxidants, produced by the inflammatory cells in the lung, can reach the systemic circulation and/or contribute to the activation of inflammatory cells during transit through the pulmonary circulation. A third possibility is that some of the aspects of the systemic immunological abnormalities in COPD patients may be a cause rather than a consequence of COPD. This possibility is based upon the following observations. Only a percentage of all smokers eventually develop COPD , suggesting that the participation of other factors, for example, genetic factors, is also important in the pathogenesis of COPD . The abnormalities seen in the neutrophils of COPD patients could be the expression of a genetic predisposition that renders these cells more susceptible to the effects of smoking and other pro-inflammatory agents. A more vigorous response to the same degree of stimulation would be the first step in a chain of reactions causing the final systemic inflammation and oxidative stress and their enhanced damaging potential.
From literature about exercise and sports it is known that exercise, if sufficiently intense, leads to a highly stereotyped immune response in healthy subjects, mediated by an interplay of metabolic, endocrine and immunological factors . Dependent on type, duration and intensity, exercise induces an increase in plasma concentrations of the stress hormones epinephrine, norepinephrine, β-endorphin, growth hormones, and cortisol . In healthy subjects, arterial plasma concentrations of epinephrine and norepinephrine increase almost linearly with the duration of the dynamic exercise and exponentially with the intensity when expressed relative to the individual’s &Vdot; o2max. In contrast, cortisol concentrations only increase in relation to exercise of long duration. The exercise-induced immune response in patients with COPD is poorly investigated. Colice et al.  investigated the hormonal response to maximal exercise in COPD patients who became hypoxic during exercise and reported that the rate of increase in epinephrine (but not norepinephrine) with maximal exercise was smaller compared with healthy subjects. In contrast, the hormonal response to exercise in normoxic COPD patients has been found comparable with the response in healthy subjects . These findings support the idea that hypoxia may interfere with the adrenal medullary response to exercise.
Regarding the interplay of systems involved in the response to exercise seen in healthy subjects and the basal immunological abnormalities seen in COPD patients, the immunological response to exercise in these patients may be very interesting. Despite variation in intensity and duration of the exercise and the fitness level between healthy subjects and COPD patients, several consistent patterns regarding the leukocyte subpopulations in blood were recently described . The response to exercise reflected an early leukocytosis in all subsets in both groups, followed by a second phase during which neutrophils gradually increased and lymphocyte concentrations rapidly fell. Although the response patterns of the inflammatory cells were similar in controls and patients, the whole leukocytosis occurred at an elevated level in the patients because of their low-grade systemic inflammation at rest. The high numbers of these cells and their function may be important in the onset of further inflammatory and oxidative cascades. For example, an increased phagocytosis and decreased oxidative burst of neutrophils in healthy subjects are functional changes that are suggested to be protective against the release of damaging mediators that induce intense inflammatory reactions . However, very recent data show an increase in the oxidative burst of neutrophils of COPD patients in response to high-intensity exercise [39, 40]. Although only hypothetically, this response might induce substantial damage to tissues by the release of free radicals. Additionally, the response to exercise involves an increased production and release of circulating inflammatory and pro-inflammatory cytokines. The circulation of high concentrations of TNF-α, IL-1β, IL-6 and IL-1 receptor antagonist after intensive exercise in athletes is even compared with a septic or traumatic response . Although a lot is known about the low-grade increases in basal cytokine concentrations in COPD patients, only two studies have investigated the effect of exercise on these mediators. Firstly, Rabinovich et al.  have shown that submaximal exercise (40% Wmax, 11 min) already induces an abnormal increase in plasma TNF-α levels in COPD patients. Supplementary, in another study , levels of IL-6 have been found to increase after both maximal and submaximal exercise (50% Wmax, 30 min) in especially muscle-wasted COPD patients compared with healthy subjects.
Besides the above-mentioned hormonal and inflammatory response, oxidative stress also plays a key role in the systemic response to exercise. In healthy subjects, only intense exercise induces glutathione oxidation in blood (reduced glutathione to oxidized glutathione) [44, 45]. However, exercise with a relative low external workload already induces glutathione oxidation in COPD patients [46, 47]. Within this oxidation, it has been shown that the endogenous enzyme xanthine oxidase plays an important role in the formation of free radicals . In the above-mentioned studies, oxidation of glutathione in patients with COPD is accompanied by an increase in lipid peroxidation (e.g., malondialdehyde, thiobarbituric acid-reactive substance), a marker for free radical-mediated tissue damage. Furthermore, recently, it has been reported that exercise induces free radical-induced DNA damage in patients with COPD . Not only in the systemic circulation, but also in the peripheral muscles, oxidative stress was elevated after exercise in patients with COPD [48, 49]. Together, these data suggest that exercise in patients with COPD induces oxidative stress that is accompanied with tissue damage, which may be involved in the ongoing immunological changes and progression of the disease.
Consequences of Systemic Inflammation and Oxidative Stress
During daily life, patients with COPD will frequently perform physical activities at a relatively high percentage of their maximal exercise capacity. Although not yet proven, it seems likely that these activities may influence both the number and function of the immunocompetent cells and the level of systemic oxidative stress. Consequently, these patients may be exposed to repeated bursts of systemic immunological responses, which may affect peripheral tissues and organs  by inducing damage or functional changes in, for example, skeletal muscles. Furthermore, it would be relevant to investigate if this exercise-induced immune response also plays a role in the decreased defense against infections in patients with COPD.
The concept that exercise intolerance in COPD patients is due to dyspnea, in turn caused by increased work of breathing secondary to airflow limitation [8, 9], was for the first time challenged by Killian et al. . They showed that many patients with COPD stop exercising because of leg fatigue rather than dyspnea. Since then, skeletal muscle dysfunction in COPD patients is seen as an important systemic effect of COPD and has been extensively studied, but its mechanism is still poorly understood. Exercise intolerance in COPD patients leads to adoption of a sedentary lifestyle, which in turn causes loss of muscle mass, reduction in force generating capacity of the muscles, and a decrease in resistance to fatigue . Consequently, the exercise capacity further decreases, resulting in progressive sedentarism. Briefly, patients fall into a vicious circle that worsens their disease state. Exercise training improves condition, muscle function, and muscle mass [53,54,55], but complete normalization of muscle physiology is often not fully achieved after rehabilitation. Therefore, it is likely that also mechanisms other than inactivity might play a role in skeletal muscle dysfunction in patients with COPD (table 3). One of the important potential mechanisms is systemic inflammation. The aforementioned low-grade systemic inflammation in patients with COPD and the elevations after exercise may increase levels of inflammation at the level of local organ systems like the liver , heart [57, 58], or skeletal muscle [42, 59]. Cytokines can affect muscle cells in a number of ways. TNF-α, for example, activates the transcription factor nuclear factor-κB and degrades myosin heavy chains through activation of the ubiquitin/proteasome complex . Dysregulation of this complex has been associated with loss of muscle function and muscle mass. Alternatively, TNF-α can activate the leukocytes and induce the expression of several genes that encode for TNF-α itself and many other pro-inflammatory cytokines, which would create a closed loop and contribute to the persistence and amplification of the inflammatory cascade . Finally, TNF-α can induce apoptosis of several cell systems , and recently, it has been shown that excessive apoptosis of muscle cells occurs in patients with COPD . Moreover, systemic inflammation (overexpression of IL-6) may also be the cause of suppression of the growth hormone/insulin-like growth factor 1 axis, as is seen in chronic diseases [63, 64], and is associated with loss of skeletal muscle . According to table 3, not only systemic inflammation, but also increased levels of systemic oxidative stress may be a potential mechanism in the pathogenesis of skeletal muscle dysfunction in COPD patients. Among other things, oxidative stress causes muscle fatigue  and supports proteolysis of muscle cells [67, 68]. Further, oxidative stress contributes to the gradual loss of muscle mass that occurs in the normal process of ageing [69, 70]. Whether this process occurs early or is accelerated in COPD patients with muscle wasting has not yet been explored.
|Table 3. Potential mechanisms of skeletal muscle dysfunction in COPD patients|
Shortly, muscle wasting and dysfunction in patients with COPD are probably caused by multiple mechanisms, including systemic inflammation and oxidative stress. Keeping this in mind, the increased systemic effects in response to exercise might negatively affect the skeletal muscles of these patients.
Changes within the immune system may influence the defense against infections. Epidemiological data on exercise training and the risk of minor illnesses such as upper airway infections have shown that the relation between physical activity and the risk of infections can be illustrated by the so called (symptom-based) J-curve . Regarding this curve, regular moderate activity will enhance resistance to infections, whereas intense exercise suppresses this resistance in the healthy population. However, symptoms of infections after exercise are never causally related to exercise-induced changes of the immune system. Whether the risk of infections in patients with COPD resembles this curve is unknown. Firstly, the susceptibility of COPD patients to respiratory infections is much higher than in healthy subjects [72, 73]. Therefore, the curve would already start at a higher risk of infections. This higher risk is accompanied with the low-grade basal systemic inflammation and oxidative stress as described before, which is even more intensified during exercise in comparison with healthy subjects. Although the function of the immunocompetent cells after exercise is not yet investigated, the intensified levels might be characteristic for a further elevated risk of infections in patients with COPD. To find out whether the relation between physical activity and the risk of infection in patients with COPD can be illustrated by a similar J-curve on a higher level or maybe by a linear or logarithmic relation (fig. 1), further investigations into the exercise-induced effects on the immune system in patients with COPD are needed, as well as causal studies on the relation between these effects and the occurrence of infections.
|Fig. 1. Possible J-curve for patients with COPD. The relationship between physical activity and infection risk in patients with COPD is unknown. Based on studies about the systemic immunology in these patients, the curve will start at a higher risk of infections than in healthy subjects. For now, it can only be speculated whether the activity level and risk of infection can be illustrated as (1) a J-curve on a higher level, (2) a linear relationship, or (3) a logarithmic relation.|
Since COPD is recognized as a systemic rather than only a pulmonary disease, the development for new therapeutic interventions has found new targets to manage this difficult disease. The presence of low-grade systemic inflammation and oxidative stress in COPD patients is the scientific rationale for the development of anti-inflammatory and antioxidative therapies. Antioxidants play an important role in the protection of tissues against free radical-mediated damage. Supplementation of effective antioxidants may repair the imbalance between oxidants and antioxidants in patients with COPD. A study of Daga et al.  showed that supplementation of vitamin E could reduce the level of systemic oxidative stress in patients with COPD. However, very recently, high doses of vitamin E supplements have also been associated with an increased risk of death . Next to the addition of antioxidants, decreasing the production of oxidants would be another possible target to reduce oxidative stress. Heunks et al.  showed that xanthine oxidase plays a role in the exercise-induced radical production in patients with COPD. Short treatment with allopurinol (inhibitor of xanthine oxidase) could prevent the exercise-induced glutathione oxidation and reduced the peroxidation of lipids. Whether allopurinol can also normalize the basal increased level of oxidative stress in COPD patients is unknown. Currently, effective antioxidants for clinical use that do not influence other physiological processes, like microbiological defense, are now in development [76,77,78]. Preventing oxidative stress and thereby avoiding free radical-mediated tissue damage in, for example, skeletal muscle might contribute to a better exercise capacity in patients with COPD. However, for now, too little evidence and knowledge about the safety of the use of supplements exists to make a statement about the general use of these therapies.
Additionally, several new treatments targeting the inflammatory process are now in clinical development . A broad spectrum of anti-inflammatory drugs is investigated, including targets against inflammatory cytokines and cell signaling inhibitors. In the meantime, there is still a lot of discussion on benefits and side effects of both oral and inhalation corticosteroids in the treatment of COPD. For a long time, it was suspected that inhalation of corticosteroids could avoid systemic effects. Cameron et al.  found a comparable systemic effect on the number of circulating leukocytes (neutrophilia and lymphopenia) with a high dose of inhalation steroids (beclomethasone dipropionate 1,000 μg) and a lower dose of oral steroids (prednisone 2.5 mg). Furthermore, Sin et al.  have recently shown that both oral administration and inhalation of fluticasone (30 mg/day and 1,000 μg/day, respectively) were effective in reducing serum C-reactive protein levels in patients with COPD.
At this moment, we have to conclude that the basic systemic abnormalities in COPD patients are poorly understood. Because of the complexity and interplay between multiple effects, causes and consequences are still difficult to define, which makes it difficult to find targets for effective and safe pharmacological therapies.
Several large-scale randomized studies have demonstrated that pulmonary rehabilitation improves exercise performance and health status in COPD patients . Additionally, one of the systemic effects, namely peripheral muscle weakness, has shown to improve after rehabilitation. It remains uncertain whether pulmonary rehabilitation affects exacerbation frequency, disease progression, mortality, or the systemic effects like inflammation and oxidative stress. Very recently, promising data about the reduction in exercise-induced oxidative stress after 8 weeks of rehabilitation in 11 patients with COPD were published . However, others [42, 83] have reported that, compared with healthy elderly people, patients with COPD showed a reduced ability to adapt to endurance training reflected in a lower capacity to synthesize reduced glutathione and an increased TNF-α expression. The effect of repeated exercises and the addition of pharmacological therapies on these parameters would be interesting. Very recently, Broekhuizen et al.  reported that the addition of supplemental polyunsaturated fatty acids (PUFA) to a pulmonary rehabilitation program improved the exercise capacity in COPD patients more than rehabilitation exclusively. Although PUFA can modulate local and systemic cytokine biology, the positive effects of PUFA on the exercise capacity could not be attributed to a decrease in systemic inflammation in this study. A PUFA-induced decrease in local inflammation could not be excluded. Therefore, further research to elucidate the mechanism behind the improved exercise capacity after PUFA intervention is needed. Additionally, it remains to be investigated whether PUFA intervention alone, without exercise training, will have a similar effect on exercise capacity in patients with COPD.
Besides pulmonary involvement, COPD is associated with systemic effects. Low-grade systemic inflammation and oxidative stress are present and abnormally increase in response to exercise. These processes may have harmful effects by inducing damage to local organs and tissues or by negatively influencing the immune system. A better understanding of the complexity of the systemic effects will aid the development of new therapies and management strategies for patients with COPD.
This study was financially supported by an unrestricted educational grant from AstraZeneca, The Netherlands.
H.A.C. van Helvoort
Radboud University Nijmegen Medical Centre
Department of Pulmonary Diseases, PO Box 9101
NL–6500 HB Nijmegen (The Netherlands)
Tel. +31 24 361 4579, Fax +31 24 361 0324, E-Mail H.vanHelvoort@long.umcn.nl
Received: July 25, 2005
Accepted after revision: October 21, 2005
Published online: January 19, 2006
Number of Print Pages : 10
Number of Figures : 1, Number of Tables : 3, Number of References : 84
Respiration (International Journal of Thoracic Medicine)
Vol. 73, No. 2, Year 2006 (Cover Date: March 2006)
Journal Editor: Bolliger, C.T. (Cape Town)
ISSN: 0025–7931 (print), 1423–0356 (Online)
For additional information: http://www.karger.com/RES