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ABSTRACT |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The present study was undertaken to test whether endurance
training in patients with COPD, along with enhancement of muscle bioenergetics, decreases muscle redox capacity as a result of recurrent episodes of cell hypoxia induced by high intensity exercise sessions. Seventeen patients with COPD (FEV1, 38 ± 4% pred;
PaO2, 69 ± 2.7 mm Hg; PaCO2,42 ± 1.7 mm Hg) and five age-matched control subjects (C) were studied pretraining and post-training. Reduced (GSH) and oxidized (GSSG) glutathione, lipid
peroxidation, and gamma-glutamyl cysteine synthase heavy subunit chain mRNA expression (
GCS-HS mRNA) were measured in
the vastus lateralis. Pretraining redox status at rest and after moderate (40% Wpeak) constant-work rate exercise were similar between groups. After training (
Wpeak, 27 ± 7% and 37 ± 18%,
COPD and C, respectively) (p < 0.05 each), GSSG levels increased
only in patients with COPD (from 0.7 ± 0.08 to 1.0 ± 0.15 nmol/
mg protein, p < 0.05) with maintenance of GSH levels, whereas
GSH markedly increased in C (from 4.6 ± 1.03 to 8.7 ± 0.41 nmol/
mg protein, p < 0.01). Post-training GCS-HS mRNA levels increased
after submaximal exercise in patients with COPD. No evidence of
lipid peroxidation was observed. We conclude that although endurance training increased muscle redox potential in healthy subjects, patients with COPD showed a reduced ability to adapt to endurance training reflected in lower capacity to synthesize GSH.
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Keywords: COPD; glutathione; muscle dysfunction; endurance training; oxidative stress
Oxidative stress is a dynamic process that reflects an imbalance between pro-oxidant and antioxidant factors in favor of the former (1). Reduced glutathione (GSH), the most abundant nonprotein thiol in cells, plays a prominent role in the regulation of this delicate balance by quenching reactive oxygen species (ROS), aimed to maintain an appropriate cellular redox environment (1, 2). GSH is synthesized exclusively in the cytosol by two sequential enzymatic steps, although it is also found in mitochondria where it plays a pivotal role in maintaining vital mitochondrial functions (3).
It has recently been reported that patients with pulmonary emphysema substantiated by CT-scan show decreased muscle antioxidant potential as indicated by low GSH levels in muscle at rest (4). During exercise, patients with chronic obstructive pulmonary disease (COPD) show higher peripheral blood (ROS) and higher oxidized glutathione (GSSG) levels than do healthy subjects (5, 6). These phenomena are partially reversed when patients exercise while breathing high O2 concentrations (5) and after pretreatment with allopurinol, a xanthine oxidase inhibitor (7). It has been suggested that muscle oxidative stress generated during exercise might be a key mechanism of the peripheral muscle dysfunction described in patients with COPD (4, 8, 9).
Endurance training enhances muscle O2 transport/O2 utilization capability, resulting in increased exercise performance both in patients with COPD (10) and in healthy sedentary subjects (10, 11). We hypothesize, however, that high intensity exercise training increases muscle oxidative stress in patients with COPD, possibly because of the inability to cope with an increased muscle ROS production. The phenomenon could be attributed to high oxygen utilization rate in mitochondrial respiratory chain (12) or by recurrent episodes of cellular hypoxia throughout the training period. Under these conditions, hypoxia is recognized as a trigger of ROS generation from different sources, including the mitochondrial respiratory chain (13) or extra-mitochondrial sources such as the xanthine oxidase system (7).
The characterization of this putative phenomenon may be of relevance in the modification of training patterns, and, more importantly, its analysis may shed light on the nature of skeletal muscle dysfunction in these patients (8).
The present investigation was designed to examine the effects of exercise training on limb muscle redox status in a
group of patients with COPD representative of a large spectrum of severity of the disease and in healthy sedentary age-matched control subjects. To this end, reduced glutathione,
GSSG, lipid peroxidation, and gamma-glutamyl cysteine
synthase heavy subunit chain mRNA expression (GCS-HS
mRNA) in muscle specimens obtained from a needle biopsy of the vastus lateralis were measured, both at rest and after moderate intensity constant-work rate exercise, before and after an 8-wk highly controlled exercise training program with cycloergometer.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Study Group
Seventeen patients with clinically stable COPD (all men) (Table 1) (14) free of oral steroids were studied. Five healthy sedentary subjects were recruited to serve as controls.
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Study Design
Selection procedures for inclusion in the study were: (1) clinical assessment; (2) pulmonary function testing at rest (MasterScreen; Jaeger, Wüerzburg, Germany) (15, 16); (3) chest radiograph; (4) general blood analysis; (5) standard incremental exercise testing. Training- induced physiologic changes were measured with exercise tolerance and half-time phosphocreatine ([PCr]) recovery with 31-phosphorus nuclear magnetic resonance spectroscopy (31P-NMRS). In all the subjects (17 patients with COPD and 5 control subjects), a needle muscle biopsy of the vastus lateralis was obtained immediately after a moderate intensity (40% pretraining Wpeak) constant-work rate protocol. In a subset of 12 patients with COPD and in all five control subjects, an additional pretraining muscle biopsy was done at rest, before the submaximal constant-work rate protocol. After training, the muscle biopsy at rest was obtained in only eight of the patients with COPD and in all five control subjects.
All subjects trained 5 d per week for 8 wk. Training sessions were split into small blocks of 2 to 5 min of high intensity continuous cycling (at approximately 90% of the Wpeak at the end of the training program) for at least an effective period of 30 min.
Exercise Testing
Incremental exercise. After 3 min of unloaded pedaling (CardiO2 cycle; Med Graphics Corp. St. Paul, MN), the work rate was increased by 5 or 10 Watts/min. Arterial blood samples (Seldicath; Plastimed, Saint-Leu-La-Foret, France) were taken every 3 min throughout the test to analyze blood gases and lactate (Ciba-Corning Diagnostics, Medfield, MA).
Half-time [PCr] recovery. Exercise tests during 31P-NMRS measurements were performed using an ergometer made of nonmagnetic materials designed to fit into a standard whole body magnet (17).
Muscle Biopsies
A muscle sample (150 mg) was obtained from the vastus lateralis using
a Bergström needle. Half of the sample was included in Kreb's buffer
(pH, 7.40) solution for immediate processing, and the remaining material was frozen in liquid nitrogen and stored at 
70° C.
The two molecular forms of glutathione, GSH and GSSG, were determined in the homogenate by high-performance liquid chromatography (HPLC) (18). Lipid peroxidation was assessed using cis-parinaric acid (CPA), a naturally fluorescent aliphatic acid containing four double bonds. This aliphatic acid incorporates readily into membranes and the loss of fluorescence upon damage of these double bonds by oxidants and reactive species monitors membranes damage (19, 20).
Gamma glutamyl cysteine synthase heavy subunit chain mRNA
expression (GCS-HS mRNA) was measured by the RT-PCR method
(21). Values for GCS-HS mRNA were corrected by 18S mRNA and
expressed as GCS-HS/18S mRNA.
Data Analysis
Results are expressed as mean ± SEM. Training effects within groups were analyzed using Student's paired t test. Comparisons between groups were made using Student's unpaired t test. Pearson's regression analysis was used when required. A p value lower than 0.05 was taken as statistically significant.
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RESULTS |
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RESULTS
DISCUSSION
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Anthropometric characteristics and lung function in both patients and control subjects are indicated in Table 1. Group mean values for age and body mass index (BMI) were similar between patients with COPD and control subjects. On average, patients showed a severe obstructive ventilatory defect, but encompassed a large spectrum of severity of the disease (FEV1 from 15 to 66% pred, PaO2 from 52 to 89 mm Hg, and BMI from 15.0 to 38.8 kg/m2).
As expected, peak exercise tolerance was severely reduced
in patients with COPD when compared with control subjects
(48 ± 6.6 versus 124 ± 14 W, respectively, p < 0.01). Although
patients with COPD showed reduced ventilatory reserve
( 
Epeak, 91 ± 7% MVV), but preserved HR reserve (HRpeak, 82 ± 3% HRmax pred), the control group displayed
normal values for these two variables (67 ± 8% and 94 ± 5%,
respectively). At peak exercise, PaO2 did not change (4 ± 3.0 mm Hg) and PaCO2 slightly increased (2 ± 4.8 mm Hg) (p < 0.001) in patients with COPD. It is of note, however, that 11 out
of the 17 patients showed exercise-induced PaO2 fall (11.36 ± 2 mm Hg) at Wpeak. The COPD group showed early increase in arterial lactate levels ([La]) (22), but [La] at peak exercise was lower in patients with COPD (5.4 mmol/L) than in control
subjects (10.8 mmol/L).
Muscle redox status at rest and after constant-work rate exercise. No differences between patients with COPD and control
subjects were seen in the resting levels of glutathione (GSH
and GSSG) in the pretraining study (Figure 1). Consistent
with this, no changes in cis-parinaric acid were found between
groups (data not shown). Eleven minutes of moderate intensity constant-work rate exercise did not generate statistically
significant changes (postexercise minus preexercise) in: (1) total glutathione levels (2.11 ± 1.8 nmol/mg protein and 0.32 ± 0.9 nmol/mg protein, control subjects (n = 5) and patients with
COPD (n = 12), respectively); and (2) lipid peroxidation index. Likewise, no differences in these variables were seen
from rest to moderate exercise after training in the two groups
(eight patients with COPD and five control subjects).
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Effects of Endurance Training
Physiologic training effects (Table 2) were shown at peak exercise in patients with COPD (Wpeak 27 ± 7%,p < 0.001;
O2peak: 9 ± 4%, p < 0.05) and in healthy subjects
(Wpeak 37 ± 18%, p = 0.07; O2peak: 15 ± 4%, p < 0.05).
Both [La] at iso-work rate and half-time [PCr] recovery significantly fell after training (Table 2). The impact of the training
program on Wpeak and whole-body O2peak was lower in patients with COPD than in control subjects, whereas training-induced effects on skeletal muscle ([La] at iso-work rate and
half-time [PCr] recovery) were similar between groups.
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Changes in muscle redox status (17 patients with COPD and
five control subjects). The levels of GSH and total glutathione (GSH+GSSG) remained unchanged in patients with COPD
after endurance training, although a moderate increase in
GSSG levels was observed (GSSG, from 0.70 ± 0.08 to 1.0 ± 0.15 nmol/mg protein, p = 0.05) (Figure 2). In contrast, training in healthy subjects increased reduced glutathione substantially (GSH, from 4.60 ± 1.03 to 8.70 ± 0.41 nmol/mg protein,
p < 0.01); and, consequently, so did total glutathione (total
glutathione, from 5.20 ± 1.09 to 9.50 ± 0.48 nmol/mg prot, p < 0.05). No increase in lipid peroxidation from pretraining to
post-training (from 398 ± 93 to 397 ± 52 AU, and from 397 ± 72 to 500 ± 85 arbitrary unit (AU), patients and control subjects respectively) was observed. Moreover, although healthy subjects showed a correlation between post-training Wpeak
and GSH, the COPD group presented an association between
Wpeak and GSSG, as displayed in Figure 3.
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Post-training GCS-HS mRNA expression (Figure 4)
showed a trend to fall in healthy subjects, whereas a tendency
to rise was seen in patients with COPD. Moreover, post-training induction of GCS-HS mRNA expression reaching statistical significance (post-minus pre-exercise difference in the post-training study: 249 ± 115 GCS-HS/18S mRNA, p < 0.05) was
observed after submaximal exercise in patients with COPD,
but not in healthy sedentary subjects. A strong correlation was
seen between training-induced fall in GCS-HS mRNA expression and post-training increase in GSH (r = 0.95, p < 0.01) in control subjects. Muscle biopsies obtained at rest
(eight patients with COPD and five control subjects) did not
show changes in the redox status from pretraining to post-training in GSH (from 5.7 ± 0.53 to 5.1 ± 0.65 and from 6.5 ± 1.30 to 8.7 ± 1.20 nmol/mg protein, patients and control subjects, respectively), in GSSG nor in total GSH in the two groups.
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DISCUSSION |
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The ability of mammalian cells to maintain cellular functions during oxidative stress depends on the induction of protective antioxidant systems. In this regard, GSH plays a recognized key role in quenching a varied repertoire of reactive species, which otherwise may compromise cell functions (1, 2). Because the cellular steady-state level of GSH reflects a balance between its synthesis and its utilization in the elimination of reactive oxygen species, the present study has characterized the regulation of GSH as a reflect of oxidative stress in skeletal muscle after a prolonged training period in healthy control subjects and in patients with COPD. Our findings indicate a divergent ability of the two groups to adapt the redox system to the cellular demand for O2 transport and consumption during training. Although healthy control subjects markedly increased muscle GSH levels after prolonged training, the levels of GSH homeostasis in skeletal muscle of patients with COPD did not undergo significant changes except for the GSSG increase detected after the training period. Despite these divergent findings, there was a lack of lipid peroxidation common for both groups, suggesting absence of significant deleterious consequences of oxidative stress after endurance training in both patients with COPD and control subjects.
Despite the fact that the GCS-HS mRNA levels showed a
trend to decrease (p = 0.09), healthy sedentary subjects adapt
to the demand of exercise training by doubling the cellular
levels of GSH. The negative correlation between the GSH
and the fall in GCS-HS mRNA levels (r = 0.95) after training is an intriguing finding; and although we do not understand the mechanisms mediating this inverse relation, we postulate that during a prolonged stimuli (8 wk of training), the
rise in GSH may signal the repression of GCS-HS mRNA.
On the other hand, we attempted to characterize the regulation of GSH at the molecular level by determining the mRNA
levels of the GCS-HS, but the lack of measurement of its enzymatic activity because the insuficient size of muscle sample limits the interpretation of our findings.
The resting muscle biopsies carried out in eight patients with COPD and in all five control subjects pretraining and post-training did not display changes in the redox system. These results seems to suggest therefore that the findings alluded to above are only evident after exercise.
It is well accepted that strenuous exercise induces higher levels of oxidative stress in patients with COPD than in normal subjects (5). The phenomenon can be inhibited by treatment with xanthine oxidase inhibitors (allopurinol) (7) and by oxygen therapy (5). In the present study, the lack of changes in the redox system after constant-work rate exercise both in patients with COPD and in control subjects (Figure 1) can be ascribed to the moderate intensity (40% pretraining Wpeak) exercise. Both intensity and duration of the protocol were chosen to perform the measurements after steady state exercise.
Training Effects and Muscle Redox Status
Patients with COPD as well as healthy sedentary subjects significantly enhanced exercise tolerance, a phenomenon dependent on training-induced improvement of muscle O2 transport
and utilization (8). It is of note that post-training values of
half-time [PCr] recovery in patients with COPD were equivalent to the pretraining results in control subjects (10) (Table
2). The present study confirms that in patients with COPD
(10), training effects on skeletal muscle (-half-time [PCr] recovery and -[La]iso-w) were noticeably higher than those
observed at whole-body level (Wpeak and O2peak), a
finding that may be of relevance in the evaluation of training outcomes.
In these patients, the reserve of the central organs to increase convective O2 transport (arterial oxygen content times
blood flow) during heavy exercise (8, 10) is limited by: (1) the severity of lung function impairment and (2) the effects of
pleural pressure swings on cardiac output ( E and QT, respectively) (23, 24). The phenomena alluded to, along with
concurrent peripheral factors such as impaired muscle oxygen
conductance from capillary to mitochondria (25, 26), are
prone to induce cell hypoxia during moderate to high intensity
exercise and consequently oxidative stress. Increased activity
of cytochrome oxidase (COX) and upregulation of this enzyme (27) can be interpreted as mitochondrial adaptations to
cell hypoxia.
Oxidative Stress and Muscle Wasting
Engelen and coworkers (4, 9) speculated on a causal relationship between abnormally low muscle redox potential at rest and the alterations of protein metabolism observed in patients with emphysema substantiated by CT-scan. Despite the fact that the present study did not identify baseline differences in GSH levels between healthy subjects and patients with COPD, our results are not in conflict with those reported by these investigators (4) since we purposely studied a heterogeneous group of patients with COPD encompassing a large spectrum of severity of the disease.
In summary, the study has demonstrated differences in training-induced adaptations of muscle redox status between patients with COPD and control subjects. Although healthy sedentary subjects increased muscle GSH levels after training, patients with COPD reduced their redox potential. Our results highlight the importance of training-induced peripheral adaptations and its relevance in the assessment of training outcomes in patients with COPD. Whether oxidative stress is a central factor mediating muscle mass wasting, particularly in susceptible subsets of patients with COPD in whom a true myopathy can be observed, remains to be elucidated.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Josep Roca, MD. Servei de Pneumologia, Hospital Clínic, Villarroel 170, Barcelona 08036, Spain. E-mail: jroca{at}clinic.ub.es
(Received in original form March 13, 2001 and accepted in revised form July 5, 2001).
Drs. Rabinovich and Troosters were Research Fellows supported by the European Respiratory Society, 2000.This article has an online data supplement, which is accessible from this issue's table of contents online at www.atsjournals.org
Acknowledgments: The writers would like to thank Felip Burgos, Conxi Gistau, and Jose Luis Valera and all the technical staff of the Lung Function Laboratory for their skillful support during the study. Anna Capitán, Cristina Gonzalez, and Eduard Vilar from EUIF Blanquerna are acknowledged for their outstanding work supervising the training sessions. They also thank Carme Hernandez, coordinator nurse of the Home Care Unit, for her support in the logistics of the study. Finally, they acknowledge the material support received from Erich Jaeger to conduct the study.
Supported by Grants FIS 99/0029 and 00/0281 from the Fondo de Investigaciones Sanitarias; E-Remedy (IST-2000-25146) from the European Union (DG XIII); and, Comissionat per a Universitats i Recerca de la Generalitat de Catalunya (1999 SGR 00228).
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METHODS
RESULTS
DISCUSSION
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T. Troosters, R. Casaburi, R. Gosselink, and M. Decramer Pulmonary Rehabilitation in Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., July 1, 2005; 172(1): 19 - 38. [Full Text] [PDF]
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E. Barreiro, B. de la Puente, J. Minguella, J. M. Corominas, S. Serrano, S. N. A. Hussain, and J. Gea Oxidative Stress and Respiratory Muscle Dysfunction in Severe Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., May 15, 2005; 171(10): 1116 - 1124. [Abstract] [Full Text] [PDF]
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W. MacNee Pulmonary and Systemic Oxidant/Antioxidant Imbalance in Chronic Obstructive Pulmonary Disease Proceedings of the ATS, April 1, 2005; 2(1): 50 - 60. [Abstract] [Full Text] [PDF]
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N. Ambrosino and S. Strambi New strategies to improve exercise tolerance in chronic obstructive pulmonary disease Eur. Respir. J., August 1, 2004; 24(2): 313 - 322. [Abstract] [Full Text] [PDF]
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C. Coronell, M. Orozco-Levi, R. Mendez, A. Ramirez-Sarmiento, J.B. Galdiz, and J. Gea Relevance of assessing quadriceps endurance in patients with COPD Eur. Respir. J., July 1, 2004; 24(1): 129 - 136. [Abstract] [Full Text] [PDF]
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C. Koechlin, A. Couillard, D. Simar, J. P. Cristol, H. Bellet, M. Hayot, and C. Prefaut Does Oxidative Stress Alter Quadriceps Endurance in Chronic Obstructive Pulmonary Disease? Am. J. Respir. Crit. Care Med., May 1, 2004; 169(9): 1022 - 1027. [Abstract] [Full Text] [PDF]
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C. Koechlin, A. Couillard, J.P. Cristol, P. Chanez, M. Hayot, D. Le Gallais, and C. Prefaut Does systemic inflammation trigger local exercise-induced oxidative stress in COPD? Eur. Respir. J., April 1, 2004; 23(4): 538 - 544. [Abstract] [Full Text] [PDF]
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M.P.K.J. Engelen, M. Orozco-Levi, N.E.P. Deutz, E. Barreiro, N. Hernandez, E.F.M. Wouters, J. Gea, and A.M.W.J. Schols Glutathione and glutamate levels in the diaphragm of patients with chronic obstructive pulmonary disease Eur. Respir. J., April 1, 2004; 23(4): 545 - 551. [Abstract] [Full Text] [PDF]
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A.W. Boots, G.R.M.M. Haenen, and A. Bast Oxidant metabolism in chronic obstructive pulmonary disease Eur. Respir. J., November 2, 2003; 22(46_suppl): 14S - 27s. [Abstract] [Full Text] [PDF]
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M. Orozco-Levi Structure and function of the respiratory muscles in patients with COPD: impairment or adaptation? Eur. Respir. J., November 2, 2003; 22(46_suppl): 41S - 51s. [Abstract] [Full Text] [PDF]
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A.M.W.J. Schols Nutritional and metabolic modulation in chronic obstructive pulmonary disease management Eur. Respir. J., November 2, 2003; 22(46_suppl): 81S - 86s. [Abstract] [Full Text] [PDF]
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A. Couillard, F. Maltais, D. Saey, R. Debigare, A. Michaud, C. Koechlin, P. LeBlanc, and C. Prefaut Exercise-induced Quadriceps Oxidative Stress and Peripheral Muscle Dysfunction in Patients with Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., June 15, 2003; 167(12): 1664 - 1669. [Abstract] [Full Text] [PDF]
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R.A. Rabinovich, M. Figueras, E. Ardite, N. Carbo, T. Troosters, X. Filella, J.A. Barbera, J.C. Fernandez-Checa, J.M. Argiles, and J. Roca Increased tumour necrosis factor-{alpha} plasma levels during moderate-intensity exercise in COPD patients Eur. Respir. J., May 1, 2003; 21(5): 789 - 794. [Abstract] [Full Text] [PDF]
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A.G.N. Agusti, A. Noguera, J. Sauleda, E. Sala, J. Pons, and X. Busquets Systemic effects of chronic obstructive pulmonary disease Eur. Respir. J., February 1, 2003; 21(2): 347 - 360. [Abstract] [Full Text] [PDF]
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