INVESTIGATIONS INTO THE GLUTAMINE-CITRULLINE-ARGININE PATHWAY IN SEPSIS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Sepsis is a significant cause of morbidity and mortality in the intensive care unit, with reported mortality rates ranging from approximately 20 to 50 percent. Because glutamine and arginine serve important physiologic and metabolic roles and are important modulators of the immune response, adequate supply of these two amino acids may be critical for survival, and both amino acids have been used as nutritional supplements in critically-ill patients. However, their metabolic fates in sepsis remain poorly characterized. These two amino acids are linked by a common metabolic pathway involving intestinal conversion of glutamine to citrulline followed by renal uptake of citrulline and conversion to arginine. In this project we will quantitate the interplay of these two amino acids along with their intermediate, citrulline, in septic patients compared to healthy controls. We propose that in septic patients, alterations in the availability and whole-body and splanchnic metabolism of glutamine will lead to decreased synthesis of citrulline and arginine. Stable isotope tracer methods will be used to test specific aspects of these hypotheses. Specific aim 1 will determine differences in the rate of glutamine conversion to citrulline and the fractional splanchnic extraction of glutamine in septic patients and healthy controls. The hypothesis is that septic patients have decreased citrulline synthesis from glutamine, and that the rate of citrulline production is directly related to the rate of splanchnic extraction of glutamine. Specific aim 2 will determine the rate of de novo arginine synthesis from its precursors, citrulline and glutamine, in septic patients and healthy controls. The hypothesis is that decreased glutamine availability leads to decreased de novo arginine synthesis in septic patients.