TUMOR-NECROSIS-FACTOR-ALPHA PRODUCES HEPATOCELLULAR DYSFUNCTION DESPITE NORMAL CARDIAC-OUTPUT AND HEPATIC MICROCIRCULATION

Although plasma levels of tumor necrosis factor (TNF) are elevated and hepatocellular dysfunction occurs even in the early hyperdynamic stag e of sepsis, the precise mechanism responsible for this dysfunction re mains unknown. Although TNF at high doses produces circulatory failure , it is not known whether the dose of TNF that does not adversely affe ct hemodynamics alters hepatocellular function. To study this, recombi nant murine TNF-alpha was infused intravenously (0.05 or 0.25 mg/kg) o ver 30 min in normal rats. At 1 and 4 h after infusion of TNF-alpha or an equivalent volume of Wine, hepatocellular function [i.e., maximum velocity (V(max)) and Michaelis constant (K(m)] was assessed using in vivo indocyanine green clearance without blood sampling. Additional pa rameters measured were as follows: cardiac output by dye dilution, hep atic microcirculation by laser Doppler flowmetry and colloidal carbon infusion, plasma TNF and interleukin-6 (IL-6) by cytokine-dependent ce llular assays, and plasma glucose enzymatically. The results indicate that although infusion of 0.05 mg/kg TNF-alpha did not affect V(max) a nd K(m), its infusion at 0.25 mg/kg produced a significant depression of hepatocellular function and markedly increased the synthesis and/or release of IL-6. TNF-a-induced hepatocellular dysfunction was not ass ociated with any significant changes in hepatic microcirculation, plas ma glucose, cardiac output, and other measured hemodynamic parameters. Thus hepatocellular dysfunction observed after TNF infusion may be du e to the direct effect of this cytokine alone or in combination with I L-6.