Glutamine metabolism in sepsis and infection.
Severe infection causes marked derangements in the flow of glutamine among organs, and these changes are accompanied by significant alterations in regional cell membrane transport and intracellular glutamine metabolism. Skeletal muscle, the major repository of glutamine, exhibits a twofold increase in glutamine release during infection, which is associated with a significant increase in endogenous glutamine biosynthesis. Despite an increase in glutamine synthetase activity in skeletal muscle, the intracellular glutamine pool becomes depleted, indicating that release rates exceed rates of synthesis. Simultaneously, the circulating pool of glutamine does not increase, indicating accelerated uptake by other organs. The liver appears to be the major organ of glutamine uptake in severe infection; studies in endotoxemic rodents have shown net hepatic glutamine uptake to increase by as much as 8- to 10-fold. This increase is due partially to increases in liver blood flow, but also to a three- to fourfold increase in hepatocyte System N activity in the liver. Cytokines and glucocorticoids mediate the increased uptake of glutamine by the liver in septic states as well as other compounds. Sepsis does not appear to induce an increase in System N gene expression, indicating that the increase in hepatic glutamine transport observed during severe infection is probably regulated at the protein level. The bowel displays a decrease in glutamine utilization during sepsis, a response that may be related to the decrease in circulating insulin-like growth factor-1 (IGF-1) levels that is characteristic of sepsis. Recent studies suggest that IGF-1 has a direct effect on stimulating glutamine transport across the gut lumen and thus may represent a therapeutic avenue for improving gut nutrition during severe infection. The cells of the immune system (lymphocytes, macrophages) are also major glutamine consumers during inflammatory states in which cell proliferation is increased. Under these conditions, glutamine availability can become rate limiting for key cell functions, such as phagocytosis and antibody production.
Karinch
A M
AM
Department of Surgery at the Penn State College of Medicine and The Milton S. Hershey Medical Center, Hershey, PA 17033, USA.
Pan
M
M
Lin
C M
CM
Strange
R
R
Souba
W W
WW
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001424:Bacterial Infections / Q000209:etiology / Q000378:metabolism*; D001692:Biological Transport; D002986:Clinical Trials as Topic; D003106:Colon / Q000378:metabolism; D004195:Disease Models, Animal; D005544:Forecasting; D005973:Glutamine / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007421:Intestine, Small / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism; D018805:Sepsis / Q000209:etiology / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D005973:Glutamine