The overall objective of this research proposal is to study the regulation of the altered lung glutamine metabolism that occurs following trauma and infection. Glutamine is the most abundant amino acid in the body and the amino acid most affected by critical illness. We hypothesize that the lungs play a key role in interorgan glutamine metabolism in normal and stress states. The consequences of this altered lung glutamine metabolism that occurs during critical illness are unknown, but glutamine may be required for endothelial cell structure and function. The experiments outlined in this proposal are designed to further elucidate the specific mediators of the altered lung glutamine metabolism that characterize catabolic disease states. This research will utilize laboratory rats to study lung glutamine metabolism in vivo and in vitro. We will determine the flux of glutamine across the lungs and how it changes during critical illness. The in vitro studies will utilize cultured pulmonary endothelial cells and alveolar type II cells to study lung glutamine metabolism. We will study the regulation of these alterations in lung glutamine metabolism by examining the effects of the glucocorticoid hormones as well as the inflammatory mediators (Tumor Necrosis Factor and Interleukin-1) of infection on whole lung and in cultured cells. The activities of the major glutamine synthetic (glutamine synthetase) and degradative (glutaminase) enzymes will be determined as well as changes in lung glutamine content. The effects of these regulators on glutamine uptake by endothelial and Type II cells will also be studied. Finally, the effect of glutamine supplemented diets on lung metabolism will be examined. This work is relevant to patients since trauma and infection are major causes of pulmonary insufficiency and are characterized by abnormal lung glutamine metabolism. An improved understanding of lung glutamine metabolism during critical illness not only provides further knowledge of the alterations in intermediary metabolism and metabolic regulation that occur in catabolic disease states, but may allow for the design of more specific nutritional formulations which are glutamine-supplemented and may more effectively support lung glutamine metabolism during critical illness.
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