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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL001518-02
Application #
3081886
Study Section
Research Manpower Review Committee (MR)
Project Start
1985-05-01
Project End
1990-04-30
Budget Start
1986-05-01
Budget End
1987-04-30
Support Year
2
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Type
Schools of Medicine
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10027
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Bazzy, A R; Donnelly, D F (1993) Diaphragmatic failure during loaded breathing: role of neuromuscular transmission. J Appl Physiol 74:1679-83
Bazzy, A R; Kim, Y J (1992) Effect of chronic respiratory load on cytochrome oxidase activity in diaphragmatic fibers. J Appl Physiol 72:266-71
Kim, Y J; Bazzy, A R (1992) Glycogen content in neonatal diaphragmatic fibers in response to inspiratory flow resistive loads. Pediatr Res 31:354-8
Feldman, J D; Bazzy, A R; Cummins, T R et al. (1991) Developmental changes in neuromuscular transmission in the rat diaphragm. J Appl Physiol 71:280-6
Bazzy, A R; Pang, L M; Akabas, S R et al. (1989) O2 metabolism of the sheep diaphragm during flow resistive loaded breathing. J Appl Physiol 66:2305-11
Akabas, S R; Bazzy, A R; DiMauro, S et al. (1989) Metabolic and functional adaptation of the diaphragm to training with resistive loads. J Appl Physiol 66:529-35
Bazzy, A R; Akabas, S R; Hays, A P et al. (1988) Respiratory muscle response to load and glycogen content in type I and II fibers. Exp Neurol 101:17-28