Undernutrition is an important complicating factor in chronic obstructive pulmonary disease (COPD) resulting in altered diaphragmatic strength and endurance, due to atrophy of fast- twitch muscle fibers corticosteroids, which are often used in COPD, also causes as well as a decrease in the oxidative capacity of atrophy of fast-twitch muscle fibers, as well as a decrease in the oxidative capacity of skeletal muscle fibers. In malnutrition, oxidative capacity of skeletal muscle fibers has been shown to be decreased, while in emphysema it has been shown to be increased. Generally a relationship exists between the fatigue resistance of a muscle and the oxidative capacity of its muscle fibers. The overall objective of this study is to determine the interactive effects of the mechanical load of emphysema, malnutrition and corticosteroids on the fatigue resistance of the diaphragm.
The specific aims are: 1) to assess the effect of severe protein calorie malnutrition (PCM), elastase induced emphysema and corticosteroid administration on diaphragm structure and function 2) to assess the combined effects of emphysema and/or corticosteroid therapy on diaphragm structure and function 3) to determine the extent to which the changes induced by malnutrition in the PCM and PCM-emphysematous animals are reversible. Adult male Sprague Dawley rats will be studied. The induction of PCM will be achieved by prolonged food deprivation over 4 weeks. Emphysema will be induced by a single intratracheal installation of pancreatic porcine elastase. Pressure-volume relationships, lung volumes and lung morphometric indices will be determined to verify the emphysematous state. Animals will be studied 1, 3 and 6 months following the installation of elastase. Dexamethasone will be administered daily over a period of 4 weeks by subcutaneous injection. A proportion of the nutritionally deprived (ND) and emphysematous -ND animals will be refed rat food and libitum over a period of 4 weeks. In all study groups and control animals, diaphragm structure and function will be studied as follows; 1) in vitro studies of an innervated diaphragm muscle strip in which both contractile and fatigue properties will be assessed. 2) Histochemical studies and diaphragm fiber type proportions and oxidative capacity of diaphram muscle fibers. 3) Diaphragmatic morphometric analysis in which cross-section al areas of muscle fibers will be accureately quantified. These studies will providee an in depth anslysis in which cross-sectional areas of muscle fibers will be accurately quantified. These studies will provide an in depth analysis of the effects of and interaction between emphysema, malnutrition and corticosteroid therapy on diaphragm fatigue resistance.
