Joaquim Gea

An Official American Thoracic Society/European Respiratory Society Statement: Update on Limb Muscle Dysfunction in Chronic Obstructive Pulmonary Disease

BACKGROUND Limb muscle dysfunction is prevalent in chronic obstructive pulmonary disease (COPD) and it has important clinical implications, such as reduced exercise tolerance, quality of life, and even survival. Since the previous American Thoracic Society/European Respiratory Society (ATS/ERS) statement on limb muscle dysfunction, important progress has been made on the characterization of this problem and on our understanding of its pathophysiology and clinical implications. PURPOSE The purpose of this document is to update the 1999 ATS/ERS statement on limb muscle dysfunction in COPD. METHODS An interdisciplinary committee of experts from the ATS and ERS Pulmonary Rehabilitation and Clinical Problems assemblies determined that the scope of this document should be limited to limb muscles. Committee members conducted focused reviews of the literature on several topics. A librarian also performed a literature search. An ATS methodologist provided advice to the committee, ensuring that the methodological approach was consistent with ATS standards. RESULTS We identified important advances in our understanding of the extent and nature of the structural alterations in limb muscles in patients with COPD. Since the last update, landmark studies were published on the mechanisms of development of limb muscle dysfunction in COPD and on the treatment of this condition. We now have a better understanding of the clinical implications of limb muscle dysfunction. Although exercise training is the most potent intervention to address this condition, other therapies, such as neuromuscular electrical stimulation, are emerging. Assessment of limb muscle function can identify patients who are at increased risk of poor clinical outcomes, such as exercise intolerance and premature mortality. CONCLUSIONS Limb muscle dysfunction is a key systemic consequence of COPD. However, there are still important gaps in our knowledge about the mechanisms of development of this problem. Strategies for early detection and specific treatments for this condition are also needed.

Wood smoke exposure and risk of chronic obstructive pulmonary disease

It was hypothesised that wood smoke exposure could be a risk factor for chronic obstructive pulmonary disease (COPD) in Spain. The present study was designed as a case–control study of 120 females requiring hospitalisation during 2001–2003 at Hospital del Mar (Barcelona, Spain). Cases were recruited from hospital records as females who had been admitted for an exacerbation of COPD. Controls were obtained from pulmonary function test laboratory consultations prior to a surgical intervention. All patients answered a standardised questionnaire. Exposure to wood or charcoal smoke was strongly associated with COPD after adjusting for age and smoking. The association between length of exposure and COPD suggested a dose–response pattern. Intensity of exposure in both summer and winter was also related to COPD. Wood or charcoal alone independently increased risk of COPD (odds ratio (OR) 1.8 and 1.5, respectively), but only the combination of both was statistically significant (OR 4.5). In conclusion, the present study shows a strong association between wood or charcoal smoke exposure and chronic obstructive pulmonary disease, supporting its existence not only in developing countries, but also in European countries, such as Spain. Further studies assessing whether this association also exists in other European societies are warranted.

Identification and prospective validation of clinically relevant chronic obstructive pulmonary disease (COPD) subtypes

Background Chronic obstructive pulmonary disease (COPD) is increasingly considered a heterogeneous condition. It was hypothesised that COPD, as currently defined, includes different clinically relevant subtypes. Methods To identify and validate COPD subtypes, 342 subjects hospitalised for the first time because of a COPD exacerbation were recruited. Three months after discharge, when clinically stable, symptoms and quality of life, lung function, exercise capacity, nutritional status, biomarkers of systemic and bronchial inflammation, sputum microbiology, CT of the thorax and echocardiography were assessed. COPD groups were identified by partitioning cluster analysis and validated prospectively against cause-specific hospitalisations and all-cause mortality during a 4 year follow-up. Results Three COPD groups were identified: group 1 (n=126, 67 years) was characterised by severe airflow limitation (postbronchodilator forced expiratory volume in 1 s (FEV1) 38% predicted) and worse performance in most of the respiratory domains of the disease; group 2 (n=125, 69 years) showed milder airflow limitation (FEV1 63% predicted); and group 3 (n=91, 67 years) combined a similarly milder airflow limitation (FEV1 58% predicted) with a high proportion of obesity, cardiovascular disorders, diabetes and systemic inflammation. During follow-up, group 1 had more frequent hospitalisations due to COPD (HR 3.28, p<0.001) and higher all-cause mortality (HR 2.36, p=0.018) than the other two groups, whereas group 3 had more admissions due to cardiovascular disease (HR 2.87, p=0.014). Conclusions In patients with COPD recruited at their first hospitalisation, three different COPD subtypes were identified and prospectively validated: ‘severe respiratory COPD’, ‘moderate respiratory COPD’, and ‘systemic COPD’.

Cigarette Smoke-induced Oxidative Stress A Role in Chronic Obstructive Pulmonary Disease Skeletal Muscle Dysfunction

RATIONALE Inflammation and oxidative stress contribute to muscle dysfunction in patients with chronic obstructive pulmonary disease (COPD). Oxidants contained in cigarette smoke (CS) induce adverse effects on tissues through oxidative phenomena. OBJECTIVES To explore oxidative stress and inflammation in quadriceps of human smokers and in diaphragm and limb muscles of guinea pigs chronically exposed to CS. METHODS Muscle function, protein oxidation and nitration, antioxidants, oxidized proteins, inflammation, creatine kinase activity, and lung and muscle structures were investigated in vastus lateralis of smokers, patients with COPD, and healthy control subjects and in diaphragm and gastrocnemius of CS-exposed guinea pigs at 3, 4, and 6 months. MEASUREMENTS AND MAIN RESULTS Compared with control subjects, quadriceps muscle force was mildly but significantly reduced in smokers; protein oxidation levels were increased in quadriceps of smokers and patients with COPD, and in respiratory and limb muscles of CS-exposed animals; glycolytic enzymes, creatine kinase, carbonic anydrase-3, and contractile proteins were significantly more carbonylated in quadriceps of smokers and patients with COPD, and in respiratory and limb muscles of CS-exposed guinea pigs. Chronic CS exposure induced no significant rise in muscle inflammation in either smokers or rodents. Muscle creatine kinase activity was reduced only in patients with COPD and in both diaphragm and gastrocnemius of CS-exposed animals. Guinea pigs developed bronchiolar abnormalities at 4 months of exposure and thereafter. CONCLUSIONS CS exerts direct oxidative modifications on muscle proteins, without inducing any significant rise in muscle inflammation. The oxidative damage to muscle proteins, which precedes the characteristic respiratory changes, may contribute to muscle loss and dysfunction in smokers and patients with COPD.

Cytokine profile in quadriceps muscles of patients with severe COPD

Background: Systemic proinflammatory cytokines and oxidative stress have been described in association with peripheral muscle wasting and weakness of patients with severe chronic obstructive pulmonary disease (COPD), but their expression in skeletal muscle is unknown. The objectives of the present study were to determine muscle protein levels of selected cytokines in patients with COPD and to study their relationships with protein carbonylation as a marker of oxidative stress, quadriceps function and exercise capacity. Methods: We conducted a cross sectional study in which 36 cytokines were detected using a human antibody array in quadriceps specimens obtained from 19 patients with severe COPD and seven healthy controls. Subsequently, selected cytokines (tumour necrosis factor (TNF)α, TNFα receptors I and II, interleukin (IL) 6, interferon γ, transforming growth factor (TGF) β and vascular endothelial growth factor (VEGF)), as well as protein carbonylation (oxidative stress index) were determined using an enzyme linked immunosorbent assay (ELISA) in all muscles. Results: Compared with controls, the vastus lateralis of patients with COPD showed significantly lower protein ELISA levels of TNFα, which positively correlated with their quadriceps function, TNFα receptor II and VEGF. Protein ELISA levels of IL6, interferon γ and TGFβ did not differ between patients and controls. Quadriceps protein carbonylation was greater in patients and inversely correlated with quadriceps strength among them. Conclusions: These findings do not support the presence of a proinflammatory environment within the quadriceps muscles of clinically and weight stable patients with severe COPD, despite evidence for increased oxidative stress and the presence of muscle weakness.

Metabolic characteristics of the deltoid muscle in patients with chronic obstructive pulmonary disease.

The purpose of this study was to analyse key enzyme activities of the deltoid muscle (DM) in chronic obstructive pulmonary disease (COPD) patients. The activities of one oxidative enzyme (citrate synthase (CS)), two glycolytic enzymes (lacatate dehydrogenase (LD); and phosphofructokinase (PFK)) and one enzyme related to the use of energy stores (creatine kinase (CK)) were determined in the DM of 10 patients with COPD and nine controls. Exercise capacity (cycloergometry) and the handgrip strength were also evaluated. Although exercise capacity was markedly reduced in COPD (57 +/- 20% predicted), their handgrip strength was relatively preserved (77 +/- 19% pred). The activity of LD was higher in the COPD patients (263.9 +/- 68.2 versus 184.4 +/- 46.5 mmol x min(-1) x g(-1), p<0.01), with a similar trend for CS (67.3 +/- 33.3 versus 46.0 +/- 17.4 mmol x min(-1) x g(-1), p = 0.07). Interestingly, the activity of the latter enzyme was significantly higher than controls if only severe COPD patients were considered (81.8 +/- 31.2 mmol x min(-1) x g(-1), p < 0.01). PFK and CK activities were similar for controls and COPD. Chronic obstructive patients show a preserved or even increased (severe disease) oxidative capacity in their deltoid muscle. This coexists with a greater capacity in the anaerobic part of the glycolysis. These findings are different to those previously observed in muscles of the lower limbs.

Physical Activity and Clinical and Functional Status in COPD

BACKGROUND The mechanisms underlying the benefits of regular physical activity in the evolution of COPD have not been established. Our objective was to assess the relationship between regular physical activity and the clinical and functional characteristics of COPD. METHODS Three hundred forty-one patients were hospitalized for the first time because of a COPD exacerbation in nine teaching hospitals in Spain. COPD diagnosis was confirmed by spirometry under stable conditions. Physical activity before the first COPD hospitalization was measured using the Yale questionnaire. The following outcome variables were studied under stable conditions: dyspnea, nutritional status, complete lung function tests, respiratory and peripheral muscle strength, bronchial colonization, and systemic inflammation. RESULTS The mean age was 68 years (SD, 9 years), 93% were men, 43% were current smokers, and the mean postbronchodilator FEV(1) was 52% predicted (SD, 16% predicted). Multivariate linear regression models were built separately for each outcome variable and adjusted for potential confounders (including remaining outcomes if appropriate). When patients with the lowest quartile of physical activity were compared to patients in the other quartiles, physical activity was associated with significantly higher diffusing capacity of the lung for carbon monoxide (Dlco) [change in the second, third, and fourth quartiles of physical activity, compared with first quartile (+ 6%, + 6%, and + 9% predicted, respectively; p = 0.012 [for trend])], expiratory muscle strength (maximal expiratory pressure [Pemax]) [+ 7%, + 5%, and + 9% predicted, respectively; p = 0.081], 6-min walking distance (6MWD) [+ 40, + 41, and + 45 m, respectively; p = 0.006 (for trend)], and maximal oxygen uptake (Vo(2)peak) [+ 55, + 185, and + 81 mL/min, respectively; p = 0.110 (for trend)]. Similarly, physical activity reduced the risk of having high levels of circulating tumor necrosis factor alpha (odds ratio, 0.78, 0.61, and 0.36, respectively; p = 0.011) and C-reactive protein (0.70, 0.51, and 0.52, respectively; p = 0.036) in multivariate logistic regression. CONCLUSIONS More physically active COPD patients show better functional status in terms of Dlco, Pemax, 6MWD, Vo(2)peak, and systemic inflammation.

Chronic endurance exercise induces quadriceps nitrosative stress in patients with severe COPD

Background: Although exercise training has beneficial effects on skeletal muscle bioenergetics and exercise performance in patients with severe chronic obstructive pulmonary disease (COPD), it may also be associated with increased quadriceps oxidative and nitrosative stress. The aim of this study was to explore quadriceps oxidative and nitrosative stress in patients with severe COPD, both before and after a 3 week endurance exercise programme, and to identify the nature of the oxidatively modified proteins. Methods: Reactive carbonyls, hydroxynonenal–protein adducts, antioxidant enzymes, nitric oxide synthase (NOS) and 3-nitrotyrosine levels were determined in the quadriceps (pre- and post-exercise) of 15 patients with severe COPD and seven healthy controls using immunoblotting (one- and two-dimensional electrophoresis), activity assays and mass spectrometry. Results: At baseline, muscle levels of reactive carbonyls, which were negatively associated with muscle strength and exercise tolerance, were significantly higher in patients than in controls. Moreover, baseline hydroxynonenal–protein adducts, superoxide dismutase activity, inducible NOS and 3-nitrotyrosine immunoreactivity levels were also significantly increased in the quadriceps of patients compared with controls. In patients, chronic exercise induced a significant rise in inducible NOS levels and a fourfold increase in protein nitration. Chronic endurance exercise induced tyrosine nitration of muscle enolase 3β, aldolase A, triosephosphate isomerase, creatine kinase, carbonic anhydrase III, myoglobin and uracil DNA glycosylase in the quadriceps of patients, while contractile protein alpha-1 actin was nitrated only in patients exhibiting muscle loss (post hoc analysis). Superoxide dismutase activity increased after the exercise programme only in controls. Conclusions: In severe COPD, chronic endurance exercise induces increased tyrosine nitration of quadriceps proteins involved in glycolysis, energy distribution, carbon dioxide hydration, muscle oxygen transfer, DNA repair and contractile function in patients exhibiting systemic effects of the disease.

Does oxidative stress modulate limb muscle atrophy in severe COPD patients

Oxidative stress may differentially regulate protein loss within peripheral muscles of severe chronic obstructive pulmonary disease (COPD) patients exhibiting different body composition. Oxidation levels of proteins, myosin heavy chain (MyHC) and myonuclei, superoxide anion, antioxidants, actin, creatine kinase, carbonic anhydrase-3, ubiquitin–proteasome system, redox-signalling pathways, inflammation and muscle structure, and damage were quantified in limb muscles of severe COPD patients with and without muscle wasting, and in sedentary controls. Compared with controls, in the quadriceps of muscle-wasted COPD patients, levels of protein carbonylation, oxidation of MyHC and myonuclei, superoxide anion production, superoxide dismutase, total protein ubiquinitation, E214k, atrogin-1, FoxO1 and p65 were higher, while content of MyHC, creatine kinase, carbonic anhydrase-3, myogenin, and fast-twitch fibre size were decreased. Importantly, in nonwasted COPD patients, where MyHC was more oxidised than in controls, its content was preserved. Muscle inflammation and glutathione levels did not differ between patients and controls. In all patients, muscle structure abnormalities were increased, while muscle force and exercise capacity were reduced. In severe COPD, while muscle oxidative stress increases regardless of their body composition, protein ubiquitination and loss of MyHC were enhanced only in patients exhibiting muscle atrophy. Oxidative stress does not seem to directly modulate muscle protein loss in these patients.

Both oxidative and nitrosative stress are associated with muscle wasting in tumour-bearing rats

Reactive oxygen and nitrogen species (ROS and RNS) have been proposed as mechanisms of cancer‐induced cachexia. In this study, we assessed using Western blot analysis the levels of total protein carbonylation (2,4‐dinitrophenylhydrazine assay), both malondialdehyde‐ (MDA‐) and 2‐hydroxy‐4‐nonenal‐ (HNE‐) protein adducts, Mn‐superoxide dismutase (Mn‐SOD), catalase, heme oxygenase‐1 (HO‐1) and 3‐nitrotyrosine formation in gastrocnemius muscles of rats bearing the Yoshida AH‐130 hepatoma. In the muscles of the tumour‐bearing animals, protein carbonylation as measured by total levels of carbonyl group formation and both HNE and MDA‐protein adducts, and protein tyrosine nitration were significantly greater than in control muscles. Protein levels of the antioxidant enzymes Mn‐SOD, catalase, and HO‐1 were not significantly modified in the rat cachectic muscles compared to controls. The inefficiency of the antioxidant enzymes in neutralizing excessive ROS production may account for elevated markers of protein oxidation and be responsible for the development of both oxidative and nitrosative stress in cancer‐induced cachexia.