Respiratory muscle function and free radicals: from cell to COPD.

Respiratory muscle dysfunction in chronic obstructive pulmonary disease (COPD) Dysfunction of the respiratory muscles, especially the diaphragm, is known to occur in patients with severe chronic obstructive pulmonary disease (COPD). Weakness of the diaphragm is part of a generalised process involving all (respiratory and peripheral) skeletal muscles. Causative factors for respiratory muscle dysfunction in COPD include disturbances in electrolytes, hypercapnia, forward failure, and prolonged use of oral corticosteroids. In addition, the altered geometry of the thorax in severe emphysema compromises the ventilatory pump function of the diaphragm. Malnutrition, which frequently occurs in moderate to severe COPD, could also play a part in respiratory muscle dysfunction. Recent studies have indicated that wasting of fat free mass in COPD is associated with peripheral skeletal muscle weakness. However, few data are available regarding the eVects of malnutrition on respiratory muscle strength. Maximal inspiratory pressure (PImax) in nutritionally depleted patients with COPD (forced expiratory volume in one second (FEV1) 45.5 (15.1)% predicted) was lower than in nondepleted patients, but this did not reach statistical significance. Little is known about the underlying mechanisms of muscle dysfunction and the structural alterations that occur in the diaphragm with COPD. Levine et al have shown that the diaphragm in patients with severe COPD (FEV1 33 (4)% predicted) has a higher proportion of type I (slow) fibres and a lower proportion of type II (fast) fibres than in those without COPD. It has recently been shown that a strong correlation exists between pulmonary functional residual capacity and the proportion of slow myosin heavy chain fibres in the diaphragm. This fast to slow fibre transition in the diaphragm can be regarded as an advantageous adaptation since it will attenuate fatiguability of the diaphragm. However, eventually most patients with COPD die from respiratory muscle failure. Apparently, at some point clinical relevant respiratory muscle dysfunction occurs in COPD. It has been shown that, besides slow to fast fibre transition, other processes also occur in the diaphragm. For instance, Campbell et al found that in 17 of 22 patients with none to moderate airway obstruction, morphological changes were present in the intercostal muscles (variation in fibre size, splitting and atrophy) but not in the latissimus dorsi muscle. Fibre atrophy was significantly correlated with airway obstruction. Hards et al also found evidence for morphological abnormalities in the internal and external intercostal muscles of patients with mild COPD. Respiratory muscle dysfunction contributes to dyspnoea and the onset of hypercapnia. The reduction in peripheral and respiratory muscle function contributes to reduced exercise tolerance. Generalised muscle weakness in these patients has been recognised as a main cause of health care utilisation. Skeletal muscles generate free radicals at rest and production increases during contractile activity. 18 Overproduction of free radicals may result in a disturbance between the pro-oxidant and antioxidant balance in favour of the former, and is called oxidative stress. This phenomenon has been found to occur in skeletal muscle under circumstances such as skeletal muscle fatigue and sepsis induced muscle dysfunction. 21 A large body of literature indicates that oxidative stress impairs skeletal muscle contractile performance. 22–25 The chronically increased load imposed on the diaphragm in severe COPD may enhance generation of free radicals which, in turn, may further impair contractility of the diaphragm. In this review we will summarise current knowledge on the role of free radicals in respiratory muscle dysfunction and discuss the relevance to patients with COPD. Possible strategies to modulate antioxidant defences in vivo will also be reviewed.