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 reg ional cell membrane transport and intracellular glutamine metabolism. Skele tal muscle, the major repository of glutamine, exhibits a twofold increase in glutamine release during infection, which is associated with a significa nt increase in endogenous glutamine biosynthesis. Despite an increase in gl utamine synthetase activity in skeletal muscle, the intracellular glutamine pool becomes depleted, indicating that release rates exceed rates of synth esis. 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 f low, but also to a three- to fourfold increase in hepatocyte System N activ ity in the liver. Cytokines and glucocorticoids mediate the increased uptak e of glutamine by the liver in septic states as well as other compounds. Se psis does not appear to induce an increase in System N gene expression, ind icating that the increase in hepatic glutamine transport observed during se vere infection is probably regulated at the protein level. The bowel displa ys a decrease in glutamine utilization during sepsis, a response that may b e 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 lu men and thus may represent a therapeutic avenue for improving gut nutrition during severe infection. The cells of the immune system (lymphocytes, macr ophages) are also major glutamine consumers during inflammatory states in w hich cell proliferation is increased. Under these conditions, glutamine ava ilability can become rate limiting for key cell functions, such as phagocyt osis and antibody production.