Depression of energy production and depletion of tissue energy stores typically accompany the increased energy demands of sepsis and traumatic injury. However, the initiators and mediators of these events, the exact nature of the energy deficits, the times when abnormalities first occur and their significance are unclear. This proposal is designed to examine the role of complement activation, cytokine production and free radical formation in the genesis of changes in cellular bioenergetics, intracellular pH, and sodium and water distribution in vivo. In animal models of sepsis, ischemia/reperfusion, and systemic inflammation, experiments are designed to determine: 1) the relationship between changes in complement activity, cytokine elaboration, and cellular energetics; 2) how complement or cytokine activity modify ATP and phosphocreatine utilization, glycolysis and glycogenolysis in skeletal muscle; 3) whether the changes in energy metabolism are initiated by the influx of sodium though membrane channels; and 4) whether specific therapy directed against complement or cytokines will enhance survival in a manner that can be related to improved energy status. Changes in water and sodium distribution will be measured using in vivo magnetic resonance spectroscopy (MRS), MRS-visible water space markers, and sodium shift reagent. Phosphocreatine breakdown rates will be measured using MRS magnetization transfer techniques and MRS-visible phosphonate water space markers. In vivo MRS will also be used to examine metabolic changes in ischemic and perfused skeletal muscle during exercise and recovery, to measure changes in the cell's energy state, and to quantitate ATP turnover. Indices of energy status in vivo will include the phosphorylation potential, free ADP concentration and the free energy hydrolysis of ATP. Experimental interventions what will be used to understand the mechanisms of the observed changes include the use of monoclonal antibodies against TNF and other cytokines, and well as complement blockade. The results obtained from these experiments would improve our understanding of the regulation of energy metabolism during stress and injury.
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