Background

Skeletal muscle wasting commonly occurs in patients with chronic obstructive pulmonary disease (COPD) and has been associated with the presence of systemic inflammation. This study investigated whether rehabilitative exercise training decreases the levels of systemic or local muscle inflammation or reverses the abnormalities associated with muscle deconditioning.

Methods

Fifteen patients with COPD (mean (SE) forced expiratory volume in 1 s 36 (4)% predicted) undertook high‐intensity exercise training 3 days/week for 10 weeks. Before and after the training programme the concentration of tumour necrosis factor α (TNFα), interleukin‐6 (IL‐6) and C‐reactive protein (CRP) in plasma was determined by ELISA, and vastus lateralis mRNA expression of TNFα, IL‐6, total insulin‐like growth factor‐I (IGF‐I) and its isoform mechanogrowth factor (MGF) and myogenic differentiation factor D (MyoD) were assessed by real‐time PCR. Protein levels of TNFα, IGF‐I and MyoD were measured by Western blotting.

Results

Rehabilitation improved peak exercise work rate by 10 (2%) (p = 0.004) and mean fibre cross‐sectional area from 4061 (254) μm2 to 4581 (241) μm2 (p = 0.001). Plasma inflammatory mediators and vastus lateralis expression of TNFα and IL‐6 were not significantly modified by training. In contrast, there was a significant increase in mRNA expression of IGF‐I (by 67 (22)%; p = 0.044), MGF (by 67 (15)%; p = 0.002) and MyoD (by 116 (30)%; p = 0.001). The increase observed at the mRNA level was also seen at the protein level for IGF‐I (by 72 (36)%; p = 0.046) and MyoD (by 67 (21)%; p = 0.012).

Conclusions

Pulmonary rehabilitation can induce peripheral muscle adaptations and modifications in factors regulating skeletal muscle hypertrophy and regeneration without decreasing the levels of systemic or local muscle inflammation.

Osteopontin (Opn) is important for T helper type 1 (TH1) immunity and autoimmunity. However, the role of this cytokine in TH2-mediated allergic disease as well as its effects on primary versus secondary antigenic encounters remain unclear. Here we demonstrate that OPN is expressed in the lungs of asthmatic individuals and that Opn-s, the secreted form of Opn, exerts opposing effects on mouse TH2 effector responses and subsequent allergic airway disease: pro-inflammatory at primary systemic sensitization, and anti-inflammatory during secondary pulmonary antigenic challenge. These effects of Opn-s are mainly mediated by the regulation of TH2-suppressing plasmacytoid dendritic cells (DCs) during primary sensitization and TH2-promoting conventional DCs during secondary antigenic challenge. Therapeutic administration of recombinant Opn during pulmonary secondary antigenic challenge decreased established TH2 responses and protected mice from allergic disease. These effects on TH2 allergic responses suggest that Opn-s is an important therapeutic target and provide new insight into its role in immunity.

Mitochondrial glucocorticoid (mtGR) and estrogen (mtER) receptors participate in the coordination of the cell’s energy requirement and in the mitochondrial oxidative phosphorylation enzyme (OXPHOS) biosynthesis, affecting reactive oxygen species (ROS) generation and induction of apoptosis. Although activation of mtGR and mtER is known to trigger anti-inflammatory signals, little information exists on the presence of these receptors in lung tissue and their role in respiratory physiology and disease. Using a mouse model of allergic airway inflammation disease and applying confocal microscopy, subcellular fractionation, and Western blot analysis we showed mitochondrial localization of GRα and ERβ in lung tissue. Allergic airway inflammation caused reduction in mtGRα, mtERβ, and OXPHOS enzyme biosynthesis in lung cells mitochondria and particularly in bronchial epithelial cells mitochondria, which was accompanied by decrease in lung mitochondrial mass and induction of apoptosis. Confirmation and validation of the reduction of the mitochondrial receptors in lung epithelial cells in human asthma was achieved by analyzing autopsies from fatal asthma cases. The presence of the mitochondrial GRα and ERβ in lung tissue cells and especially their reduction in bronchial epithelial cells during allergic airway inflammation suggests a crucial role of these receptors in the regulation of mitochondrial function in asthma, implicating their involvement in the pathophysiology of the disease.