Carlos Coronell

Relevance of assessing quadriceps endurance in patients with COPD

The aims of this study were to investigate whether the impairment in endurance of limb muscles is a general finding in chronic obstructive pulmonary disease (COPD) patients, affecting even those with mild-to-moderate disease or relatively normal physical activity. In addition, this study aimed to determine the physiopathology of exhaustion in local endurance tests and whether the reduction in quadriceps endurance can be predicted from muscle strength measurements. A total of 75 volunteers were assigned to one of two groups according to pulmonary function tests: COPD patients or healthy age-matched controls. Functional assessment included both quadriceps strength (maximum voluntary contraction (QMVC)), and quadriceps endurance (contractions against a load equivalent to 10% QMVC until task failure or for up to a limiting time of 30 min (QTlim)). COPD patients showed a decrease of ∼43% in QMVC and ∼77% in QTlim compared with controls. Task failure occurred only in COPD patients and was due to muscle fatigue, since limiting symptoms were associated with a decrease in the median frequency of quadriceps electromyographical signal and a reversible decrease in QMVC. The impairment in skeletal muscle endurance was present even in patients with mild-to-moderate airflow obstruction and individuals with relatively normal physical activity, and was irrespective of lung function variables, anthropometrical data or quadriceps strength. Peripheral muscle endurance was impaired in chronic obstructive pulmonary disease patients, even in those with relatively normal physical activity and mild-to-moderate airflow obstruction. This impairment associated with an early onset of muscle fatigue and could not be predicted from the severity of the disease or the reduction in quadriceps strength.

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.

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.

Sustained CTL activation by murine pulmonary epithelial cells promotes the development of COPD-like disease

Chronic obstructive pulmonary disease (COPD) is a lethal progressive lung disease culminating in permanent airway obstruction and alveolar enlargement. Previous studies suggest CTL involvement in COPD progression; however, their precise role remains unknown. Here, we investigated whether the CTL activation receptor NK cell group 2D (NKG2D) contributes to the development of COPD. Using primary murine lung epithelium isolated from mice chronically exposed to cigarette smoke and cultured epithelial cells exposed to cigarette smoke extract in vitro, we demonstrated induced expression of the NKG2D ligand retinoic acid early transcript 1 (RAET1) as well as NKG2D-mediated cytotoxicity. Furthermore, a genetic model of inducible RAET1 expression on mouse pulmonary epithelial cells yielded a severe emphysematous phenotype characterized by epithelial apoptosis and increased CTL activation, which was reversed by blocking NKG2D activation. We also assessed whether NKG2D ligand expression corresponded with pulmonary disease in human patients by staining airway and peripheral lung tissues from never smokers, smokers with normal lung function, and current and former smokers with COPD. NKG2D ligand expression was independent of NKG2D receptor expression in COPD patients, demonstrating that ligand expression is the limiting factor in CTL activation. These results demonstrate that aberrant, persistent NKG2D ligand expression in the pulmonary epithelium contributes to the development of COPD pathologies.

Upregulation of pro-inflammatory cytokines in the intercostal muscles of COPD patients

Muscle dysfunction is a characteristic feature of chronic obstructive pulmonary disease (COPD). Recent studies suggest that cytokines may operate as local regulators of both muscle function and regeneration. The aim of the present study was to characterise the expression of different cytokines in the external intercostal muscle of COPD. Muscle biopsies were obtained from 25 stable COPD patients and eight healthy controls. Local tumour necrosis factor (TNF)-α, interleukin (IL)-1β, -6 and -10 expressions (real-time PCR and ELISA), sarcolemmal damage (immunohistochemistry), and the transcript levels of CD18 were assessed. Muscle TNF-α and IL-6 transcripts were significantly higher in COPD patients compared with controls, and IL-1β and sarcolemmal damage showed a strong tendency in the same direction. Similar results were observed at protein level. The CD18 panleukocyte marker was similar in COPD and controls. Respiratory muscle function was impaired in COPD patients and it correlated to both the severity of lung function impairment and TNF-α muscle expression. Chronic obstructive pulmonary disease is associated with the upregulation of pro-inflammatory cytokines in the intercostal muscles. This phenomenon might be involved in respiratory muscle dysfunction.

Síndrome de bajo peso asociado a la EPOC en nuestro medio

Introduccion La enfermedad pulmonar obstructiva cronica (EPOC) es una entidad de elevada prevalencia, con importantes consecuencias economicas y sanitarias, que derivan en gran parte de la limitacion que la enfermedad comporta en la actividad y expectativas vitales del paciente. Uno de los factores recientemente implicados en las citadas limitaciones es la presencia de bajo peso asociada con la enfermedad. Aunque la causa no esta clara, esta alteracion parece afectar a un numero importante de pacientes (entre el 25 y el 35% segun las series), al menos en el norte de Europa y los EE.UU. Sin embargo, existe la percepcion de que la situacion podria ser diferente en el area mediterranea. Objetivo Aproximar la prevalencia del sindrome de bajo peso en pacientes con EPOC de nuestro entorno. Metodo Se revisaron las caracteristicas antropometricas basicas de los pacientes con EPOC filiados funcionalmente en nuestro laboratorio a lo largo de los dos ultimos anos (2000–2001). Resultados De los 3.126 sujetos analizados, la prevalencia de un indice de masa corporal (IMC) por debajo de 20 kg/m2fue de tan solo el 6,6%, cifra que se reducia al 3,1% si el dintel escogido era el de 18 kg/m2. Este dato es aun mas llamativo si se tiene en cuenta que casi la mitad de los pacientes evidenciaban enfermedad grave (volumen espiratorio forzado en el primer segundo [FEV1] inferior al 50% ref). El IMC se correlaciono directamente con FEV1/FVC y transferencia del CO. Conclusiones Estos resultados sugieren que los pacientes con EPOC de nuestra area geografica presentan caracteristicas fenotipicas diferenciadas de las previamente descritas en otras latitudes. En concreto, una menor prevalencia del sindrome de bajo peso. Sin embargo, esta observacion debe ser confirmada en estudios mas amplios.

Disfunción muscular global durante la exacerbación de la EPOC: un estudio de cohortes

Fundamento y objetivo El objetivo del presente estudio fue evaluar de forma prospectiva los efectos de una exacerbacion clinica de la enfermedad pulmonar obstructiva cronica (EPOC) sobre la funcion muscular esqueletica periferica y respiratoria Pacientes y metodo Se selecciono a 49 pacientes (todos varones con una edad media [DE] de 63 [11] anos), asignados a 3 cohortes para el analisis: a) pacientes con EPOC hospitalizados por exacerbacion de su enfermedad en sala convencional; b) pacientes hospitalizados en sala convencional por otra enfermedad pulmonar o nodulo pulmonar, y c) pacientes con EPOC en fase estable (ambulatorios). Se realizaron mediciones secuenciales mediante antropometria, bioquimica serica y bioimpedancia corporal. En la cohorte de pacientes con EPOC agudizada se evaluaron los cambios en la funcion de los musculos perifericos (fuerza y resistencia de las manos dominante y no dominante), asi como de los musculos inspiratorios y espiratorios Resultados Se evaluo a los pacientes durante un periodo medio de 6 (2) dias. Los pacientes con EPOC exacerbada mostraron un deterioro funcional muscular, progresivo y global, expresado como disminucion de la presion espiratoria maxima del 17% (12%), de la fuerza maxima de la mano dominante del 6% (9%) y de la no dominante del 7% (8%), asi como de la resistencia anaerobica de la mano dominante del 28% (26%) y de la no dominante del 23% (16%). Estos cambios tuvieron una tendencia lineal. La bioimpedancia corporal expreso una perdida media de masa magra del 7% (6%) (p Conclusiones La agudizacion de la EPOC se asocia a un deterioro agudo y global de la funcion de los musculos esqueleticos espiratorios y perifericos. Es posible que estos cambios esten relacionados con una perdida aguda de masa muscular (proteolisis). Esta disfuncion muscular no se detecta si se evalua unicamente la funcion muscular inspiratoria, probablemente por la coexistencia de factores mecanicos transitorios

Injury of peripheral muscles in smokers with chronic obstructive pulmonary disease.

Muscle injury has clinical relevance in diseased individuals because it is associated with muscle dysfunction in terms of decreased strength and/or endurance. This study was aimed at answering three questions: whether the presence of chronic obstructive pulmonary disease (COPD) is associated with peripheral muscle injury; whether muscle injury is associated with some of the relevant functional impairment in the muscles; and whether muscle injury can be solely justified by deconditioning. Twenty-one male COPD patients were eligible for the study. Seven healthy volunteers recruited from the general population were included as controls. Function of the quadriceps muscle was assessed through specific single-leg exercise (strength and endurance). Cellular (light microscopy) and subcellular (electron microscopy) techniques were used to evaluate muscle injury on biopsies from the vastus lateralis muscle. Signs of injury were found in muscles from both control and COPD patients, not only in cases showing severe airflow obstruction but also in the mild or moderate stages of the disease. Current smoking and presence of COPD were significantly associated with increased injury of the muscle as assessed by light and electron microscopy techniques. The authors conclude that peripheral muscle injury is evident in mild, moderate, and severe stages of COPD even in the absence of respiratory failure, hypercapnia, chronic steroid treatment, low body weight, or some coexisting disease. These findings support the theory that systemic factors with deleterious effect are acting on peripheral muscles of smokers with COPD, increasing the susceptibility of the muscle fibers to membrane and sarcomere injury.

Inflammatory Cytokines and Repair Factors in the Intercostal Muscles of Patients With Severe COPD

a b s t r a c t Objective: There is disagreement regarding the local action of cytokines in the respiratory muscles of patients with chronic obstructive pulmonary disease (COPD). The objective of this study was to analyze the relationships between cytokine expression and genetic activation of the mechanisms of muscle repair. Patients and Methods: Twenty-five patients with severe COPD and in stable condition were enrolled in the study. We performed a biopsy of the external intercostal muscle of the patients and analyzed the specimen for signs of muscle lesion (morphometry), infiltration of inflammatory cells (immunohistochemistry), and expression of selected genes (real-time polymerase chain reaction technique) corresponding to the cytokines (tumor necrosis factor α (TNF-α) and its type 1 and 2 receptors (TNFR1 and TNFR2), and interleukin (IL) 1β, IL-6, and IL-10), a pan-leukocyte marker (CD18), and key molecules in the repair- myogenesis pathways (Pax7, M-cadherin, and MyoD). Results: Expression of TNFR2 is directly related to inspiratory muscle function (represented by maximum sustainable inspiratory pressure; r=0.496; P<.05), whereas expression of CD18 is inversely related (r=0.462; P<.05). Moreover, expression of the 2 TNF-α receptors was directly related to that of the key molecules of the repair pathways analyzed (TNFR1 to Pax7 (r=0.650; P<.001) and M-cadherin (r=0.678; P<.001); TNFR2 to Pax7 (r=0.395; P<.05), M-cadherin (r=0.409; P<.05), and MyoD (r=0.418; P<.05)). Conclusions: Expression of TNF-α receptors bears a close relationship both to activation of the myogenesis programs and to inspiratory muscle function. This reinforces our hypothesis that some local cytokines take part in the repair of respiratory muscles in patients with COPD.

Citocinas inflamatorias y factores de reparacion en los musculos intercostales de pacientes con EPOC grave

OBJECTIVE There is disagreement regarding the local action of cytokines in the respiratory muscles of patients with chronic obstructive pulmonary disease (COPD). The objective of this study was to analyze the relationships between cytokine expression and genetic activation of the mechanisms of muscle repair. PATIENTS AND METHODS Twenty-five patients with severe COPD and in stable condition were enrolled in the study. We performed a biopsy of the external intercostal muscle of the patients and analyzed the specimen for signs of muscle lesion (morphometry), infiltration of inflammatory cells (immunohistochemistry), and expression of selected genes (real-time polymerase chain reaction technique) corresponding to the cytokines (tumor necrosis factor alpha [TNF-alpha] and its type 1 and 2 receptors [TNFR1 and TNFR2], and interleukin [IL] 1beta, IL-6, and IL-10), a pan-leukocyte marker (CD18), and key molecules in the repair-myogenesis pathways (Pax7, M-cadherin, and MyoD). RESULTS Expression of TNFR2 is directly related to inspiratory muscle function (represented by maximum sustainable inspiratory pressure; r=0.496; P<.05), whereas expression of CD18 is inversely related (r=0.462; P<.05). Moreover, expression of the 2 TNF-alpha receptors was directly related to that of the key molecules of the repair pathways analyzed (TNFR1 to Pax7 [r=0.650; P<.001] and M-cadherin [r=0.678; P<.001]; TNFR2 to Pax7 [r=0.395; P<.05], M-cadherin [r=0.409; P<.05], and MyoD [r=0.418; P<.05]). CONCLUSIONS Expression of TNF-alpha receptors bears a close relationship both to activation of the myogenesis programs and to inspiratory muscle function. This reinforces our hypothesis that some local cytokines take part in the repair of respiratory muscles in patients with COPD.