THE ACUTE EFFECTS OF TNF-ALPHA ON THE ISOLATED-PERFUSED RAT-LIVER

Background: TNF-alpha mediates the hepatic response to sepsis by mecha nisms which are not well understood, TNF-alpha is known to stimulate t he hepatocellular uptake of specific amino acids in vivo; however, lit tle is known about the direct effects of TNF-alpha on hepatic amino ac id or glutathione homeostasis, which is a potential factor in the acut e hepatic response to sepsis. Methods: Using the isolated perfused rat liver, we characterized the effects of TNF-alpha on the secretion of amino acids and glutathione into bile and perfusate. Livers taken from adult male Sprague-Dawley rats were perfused with TNF-alpha at a dose of 1 or 2 mu g. Bile and perfusate were collected for the quantitatio n of amino acid and glutathione concentrations. Results: Administratio n of 2 mu g TNF-alpha resulted in significant increases in biliary and perfusate concentrations of branched chain, gluconeogenic, and total amino acids, TNF-alpha was also associated with dose-related increases in oxygen uptake, and greater biliary concentrations of glutathione. Conclusion: TNF-alpha has direct effects upon hepatic amino acid metab olism, which represent some of the early events involved in the mechan ism of response to sepsis.