Diaphragm function in animal models of chronic obstructive pulmonary disease.
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RU Radboud Universiteit Nijmegen, 28 maart 2008
Promotor : Dekhuijzen, P.N.R. Co-promotor : Heunks, L.M.A.
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SubjectUMCN 4.1: Microbial pathogenesis and host defense
COPD is characterized by progressive and irreversible airway obstruction. The diaphragm is the main inspiratory muscle. In patients with COPD, structural and functional alterations are present in this skeletal muscle. Dysfunction of respiratory muscles limits the exercise capacity and activities of daily living in these patients and it increases the need for- and cost of medical care. In this thesis we investigated some mechanisms in skeletal dysfunction in COPD. The underlying mechanisms limiting diaphragm function in COPD are divers. Hypoxemia is a common feature in severe COPD. Skeletal muscle performance, measured by force generation and resistance to fatigue, are negatively influenced by hypoxia. Although mechanisms of impaired muscle contractility during hypoxia are incompletely understood, free radicals appear to play an important role. Specific intracellular targets for free radicals are located on the RyR Ca2+ release channel and on the contractile apparatus. Modulation of redox balance of reactive thiols located on the RyR-channels by NO reduces Ca2+-release from the sarcoplasmic reticulum. Free radicals generated by xanthine oxidase do not affect rat diaphragm contractility under either hypoxic or hyperoxic conditions. In light microscopy and on the ultrastructural level we showed morphological changes in the emphysematous diaphragm as a sign of increased resistive load. Besides, functional adaptations occur in the emphysematous diaphragm. Diaphragm fatigue may be the result of a failure of the muscle itself to generate force or a failure in neuromuscular transmission. The contribution of neuromuscular transmission failure to total diaphragm fatigue decreases during repeated isometric and isotonic contractions compared to control.
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