Although hepatocellular function is depressed early following trauma and heraorrhagic shock (which are associated with low flow conditions and tissue hypoxia) as well as following TNF infusion, the precise mechanism responsible for the hepatocellular dysfunction remains unknown. To study this, rats (275-325g) were placed in a plastic box which was flushed with a gas mixture containing 6.3% O2:93.7% N2 or room air (i.e., control group) for 1 h, followed by return of the animals to room air. At 0 and 4 h after hypoxemia, hepatocellular function [i.e., maximum velocity of indocyanine green clearance (VJ and the efficiency of the active transport (Km)J was measured using an in vivo hemoreflectometer. Cardiac output was determined by dye dilution technique. Hepatic microvascular blood flow was assessed by laser Doppler flowmetry. Plasma PGE2 and IL-6 were measured by RIA and bioassay, respectively. The results indicate that hypoxemia in the absence of blood loss produced hepatocellular depression (i.e., decreased Vmax by 44-50% and Km, by 55-68%, respectively) despite stable cardiac output and hepatic microcirculation. Moreover, hypoxemia resulted in a significant increase in circulating levels of PGE2 (by 38%, only at 0 h after hypoxia) as well as IL-6 (by 372-389%, respectively). Thus, hypoxemia observed after trauma and hemorrhagic shock appears to be responsible for producing hepatocellular dysfunction through upregulation of PGE2 and/or IL-6. In view of this, long-lasting hypoxemia in trauma victims should be avoided, perhaps by early intubation and ventilation so that the potential additional proinflammatory cytokine and PGE2 release (which further depresses the hepatocellular function under those conditions) can be prevented.