The applicant's long-term goal is to pursue an academic career in pediatric chest medicine. The applicant plans to develop expertise in respiratory muscle function with special emphasis on the basic biochemical metabolic and structural mechanisms which are responsible for the adaptation of the respiratory muscles to increased work load. Using a model of respiratory muscle fatigue in chronically instrumented unanesthetized sheep, this proposal addresses basic mechanisms and will focus on the study of a) neural to mechanical interaction in the diaphragm, b) substrate (carbohydrates and lipids) availability and utilization and their relation to function, c) the effects of perturbations such as increased respiratory load and chronic hypoxia on a) & b) above, and d) the relation of structure to function with respect to maturation of respiratory muscles in early life. Using state of the art techniques, physiologic indices (Pdi, diaphragm EMG, ventilation and arterial blood gases) will be measured during inspiratory and expiratory flow resistive loaded breathing. The force generated by the diaphragm (strain gauge transducers) will be related to the operating length of the diaphragm (sonomicrometry, inductance coils) and to Pdi. Using histochemical, morphometric and biochemical techniques, diaphragmatic utilization of glucose, free fatty acids, and intramuscular glycogen and triglyceride will be determined (phrenic vein catheterization, Fick principle) and the enzymes responsible for their utilization will be studied. Oxygen consumption and blood flow to the diaphragm (microsphere method) will be measured. Endurance of the diaphragm will be examined when the intercostal muscles are denervated and when the vagus nerve is blocked (vagal trunk cooling or local anesthesia). Endurance of the diaphragm and its structural and biochemical properties will be studied after exposure to chronic hypoxia. In addition, to better understand the susceptibility of the young to respiratory muscle fatigue, these studies will be performed in the young lamb. Understanding the structural, biochemical and physiologic changes in the respiratory muscles associated with acute and chronic stress is likely to generate new concepts for the prevention and treatment of respiratory muscle fatigue and respiratory failure.
