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Patients with severe trauma injury are transiently exposed to increased serum concentrations of tumor necrosis factor-[Alpha] (TNF-[Alpha]). These patients are susceptible to the development of multisystem organ failure (MSOF) triggered by subsequent exposure to bacterial toxins either via infection or increased intestinal permeability. We simulated the cytokine response of trauma by infusing 0.8 or 8.0 [micro]g/kg of TNF-[Alpha] (priming dose) into chronically catheterized rats. After 48 h, rats were challenged with endotoxin [lipopolysaccharide (LPS); 10 or 1,000 [micro]g/kg]. Animals primed with either dose of TNF-[Alpha] and then challenged with 1,000 [micro]g/kg of LPS demonstrated significantly increased mortality, mean peak serum concentrations of interferon-[Gamma] (IFN-[Gamma]), and blood lactate concentrations (P [is less than] 0.05) compared with nonprimed animals. Mean peak serum concentrations of IFN-[Gamma] and blood lactate concentrations were increased after challenge with 10 [micro]g/kg of LPS only in animals primed with 8.0 [micro]g/kg of TNF-[Alpha]. Priming with TNF-[Alpha] did not increase mortality after challenge with 10 [micro]g/kg of LPS. These data suggest that both TNF-[Alpha] release and the subsequent exposure to bacterial toxins mediate the pathophysiological progression from trauma to subsequent MSOF. septic shock; priming; interferon-[Gamma]; endotoxin; lactate

Staphylococcal enterotoxin B potentiates LPS-induced hepatic dysfunction in chronically catheterized rats. Am J Physiol Gastrointest Liver Physiol 280: G866-G872, 2001.--Most models of liver dysfunction in sepsis use endotoxin (lipopolysaccharide; LPS) to induce a pathophysiological response. In our study published in this issue (Beno DWA, Uhing MR, Goto M, Chen Y, Jiyamapa-Serna VA, and Kimura RE. Am J Physiol Gastrointest Liver Physiol 280: G858-G865, 2001), the adverse effect of LPS on hepatic function in vivo was only significant at relatively high LPS doses despite high tumor necrosis factor-[Alpha] concentrations. However, many patients with sepsis are exposed to multiple bacterial toxins that may augment the immune response, resulting in increased hepatic dysfunction. We have developed a model of polymicrobial sepsis by parentally administering a combination of staphylococcal enterotoxin B (SEB) and LPS. Using this model, we demonstrate that SEB (50 [micro]g/kg) potentiates the effect of LPS-induced hepatic dysfunction as measured by decreased rates of biliary indocyanine green clearance and bile flow. These increases were most pronounced with doses of 10 and 100 [micro]g/kg LPS, doses that by themselves do not induce hepatic dysfunction. This may explain the seemingly increased incidence and severity of liver dysfunction in sepsis, and it suggests that the exclusive use of LPS for replicating septic shock may not be relevant for studies of hepatic dysfunction. interferon-[Gamma]; hepatocellular dysfunction; sepsis; cholestasis; in vivo studies

Endotoxin-induced reduction in biliary indocyanine green excretion rate in a chronically catheterized rat model. Am J Physiol Gastrointest Liver Physiol 280: G858-G865, 2001.--Using a nonstressed chronically catheterized rat model in which the common bile duct was cannulated, we studied endotoxin-induced alterations in hepatic function by measuring changes in the maximal steady-state biliary excretion rate of the anionic dye indocyanine green (ICG). Biliary excretion of ICG was calculated from direct measurements of biliary ICG concentrations and the bile flow rate during a continuous vascular infusion of ICG. Despite significant elevations in mean peak serum tumor necrosis factor-[Alpha] (TNF-[Alpha]) concentrations (90.9 [+ or -] 16.2 ng/ml), there was no effect on mean rates of bile flow or biliary ICG clearance after administration of 100 [micro]g/kg endotoxin at 6 or 24 h. Significant differences from mean baseline rates of bile flow and biliary ICG excretion did occur after administration of 1,000 [micro]g/kg endotoxin (mean peak TNF-[Alpha] 129.6 [+ or -] 24.4 ng/ml). Furthermore, when rats were treated with up to 16 [micro]g/kg of recombinant TNF-[Alpha], there was no change in mean rates of bile flow or ICG biliary clearance compared with baseline values. These data suggest that the complex regulation of biliary excretion is not mediated solely by TNF-[Alpha]. tumor necrosis factor-[Alpha]; hepatocellular dysfunction; sepsis; cholestasis; in vivo studies