The acute effects of TNF-α on the isolated perfused rat liver

Background: TNF-α mediates the hepatic response to sepsis by mechanisms which are not well understood. TNF-α is known to stimulate the hepatocellular uptake of specific amino acids in vivo; however, little is known about the direct effects of TNF-α on hepatic amino acid or glutathione homeostasis, which is a potential factor in the acute hepatic response to sepsis. Methods: Using the isolated perfused rat liver, we characterized the effects of TNF-α on the secretion of amino acids and glutathione into bile and perfusate. Livers taken from adult male Sprague-Dawley rats were perfused with TNF-α at a dose of 1 or 2 μg. Bile and perfusate were collected for the quantitation of amino acid and glutathione concentrations. Results: Administration of 2 αg TNF-α resulted in significant increases in biliary and perfusate concentrations of branched chain, gluconeogenic, and total amino acids. TNF-α was also associated with dose-related increases in oxygen uptake, and greater biliary concentrations of glutathione. Conclusion: TNF-α has direct effects upon hepatic amino acid metabolism, which represent some of the early events involved in the mechanism of response to sepsis.