Inflammatory cells and apoptosis in respiratory and limb muscles of patients with COPD

Abstract

Discrepancies exist regarding the involvement of cellular inflammation and apoptosis in the muscle dysfunction of chronic obstructive pulmonary disease (COPD) patients with preserved body composition. We explored whether levels of inflammatory cells and apoptosis were increased in both respiratory and limb muscles of COPD patients without nutritional abnormalities. In the vastus lateralis, external intercostals, and diaphragms of severe and moderate COPD patients with normal body composition, and in healthy subjects, intramuscular leukocytes and macrophage levels were determined (immunohistochemistry). Muscle structure was also evaluated. In the diaphragm and vastus lateralis of severe and moderate COPD patients and controls, apoptotic nuclei were explored using the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, electron microscopy, and caspase-3 expression. In COPD patients compared with controls, diaphragm and intercostal levels of inflammatory cells were extremely low and not significantly different. However, in the vastus lateralis of the severe patients, inflammatory cell counts, although also very low, were significantly greater. In those patients, TUNEL-positive nuclei levels were also significantly greater in diaphragms and vastus lateralis. A significant inverse relationship was found between quadriceps TUNEL-positive nuclei levels and muscle force. Ultrastructural apoptotic nuclei revealed no differences in respiratory or limb muscles between COPD patients and controls. Muscle caspase-3 expression did not differ between patients and controls. In severe COPD patients with preserved body composition, while increased apoptotic nuclei seems to be a contributor to their muscle dysfunction, cellular inflammation does not. The increased numbers of TUNEL-positive nuclei in their muscles suggest that they may also be exposed to a continuous repair/remodeling process.

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

“…Nevertheless, there is no strong relationship between muscle oxidative stress and local inflammation in patients with COPD (171,223,233,236). In fact, although local and systemic levels of inflammatory mediators are relatively low in patients with COPD regardless of their body composition, evidence of strong oxidative stress is consistently found in limb muscles and in the blood of these patients (171,217,223,232,233,236). This specific issue is covered in more detail in a section below (MECHANISMS OF LIMB MUSCLE DYSFUNCTION IN COPD).…”

“…Preferential use of glycolysis and accumulation of muscle metabolites associated with muscle fatigue (179,180,190,199,443) AMERICAN THORACIC SOCIETY DOCUMENTS Increased Nedd4 expression compromises satellite cell proliferation and muscle regeneration by favoring ubiquitination and degradation of Notch (326), an important transcription factor involved in the regulation of these processes (327). Conflictual or negative results regarding apoptosis and macroautophagy in the muscles of COPD demand further studies to explore the role of these mechanisms (102,189,236). Although increased inflammatory response is seen during exacerbated COPD (328,329), similar observation is controversial in stable patients (201,232,(330)(331)(332).…”

Physical activity, nutritional status and systemic inflammation in COPD

“…Systemic inflammation and oxidative/nitrosative stress have been described among these pathogenic mechanisms responsible for muscle dysfunction in COPD [42,43]. The presence of markers of local inflammation at muscle level is less clear and yet a debatable issue [36,[44][45][46][47][48]. COPD is, thus, a disease of the lungs with extrapulmonary manifestations, among which skeletal muscle dysfunction is an independent prognosis factor and it is responsible, in part, for exercise intolerance in these patients [28-30, 40, 41, 43].…”

Alterations in Nutritional Status and Body Composition in COPD Patients

“…Both phenomena are closely interrelated and have been demonstrated in COPD patients, both at the systemic level and in lungs, muscles, and adipose tissue 24,49,50,56 . Their deleterious action may be direct or through the activation of other biological processes and metabolic pathways that also favour disturbances in nutritional status.…”