Chronic obstructuve lung disease (COPD) alters the length and alignment of the respiratory muscles and causes generalized body wasting. We believe that the respiratory muscle response(s) to COPD: 1) depend on the interplay of mechanical factors (which determine muscle length and load) and nutritional and humoral factors (which affect protein synthesis and degradation); 2) vary from one respiratory muscle to another depending on the relative importance of the above factors; and 3) may be modified nutritionally and pharmacologically. These hypotheses will be tested in a well accepted animal model of emphysema (intracheal injection of elastase in the hamster). Studies will be performed to examine the effect of COPD on the components of the respiratory musculoskeletal system in vitro and their integrated behavior in situ. The intrinsic contractile properties (i.e. length-tension, force-frequency, force-velocity, and tension-time relationships) of the inspiratory and expiratory muscles of the rib cage, abdominal wall, and neck will be examined in isolated muscle strips in vitro and correlated with muscle structure and the dimensions and impedance of the rib cage. The length of the actin and myosin contractile proteins and their zone of overlap and the number of sarcomeres in series along the muscle fiber will be measured using transmission electron microscopy. The percentage and cross sectional area of histochemically stained slow oxidative, fast oxidative and fast glycolytic muscle fibers will be determined. The mechanical properties of the rib cage which affect muscle length, load, and alignment will be assessed from the dimensions of the isolated rib cage, its stress-strain relationship, and three dimensional pattern of movement. Muscle length, configuration and alignment in situ will also be assessed. In particular the shape of the diaphragm and the area of its zone of apposition with the chest wall will be quantitated. The effects of nutritional deprivation and supplementation on the respiratory muscle responses to COPD will be assessed from muscle structure and rates of protein synthesis and degradation. Muscle protein synthesis and degradation will be assessed in isolated tissues from the uptake and release of labeled amino acids from incubation medium. Indices of muscle protein metabolism will be correlated with muscle structure. The role played by interleukin-1 (IL-1), a hormone mediator of inflammation, in causing respiratory muscle atrophy will be examined. IL-1 activity of plasma, urine, and bronchoalveolar cells will be assessed using the murine thymocyte activation method.
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