The pro-inflammatory cytokine tumor necrosis factor (TNF) is dramatically and transiently elevated in the circulation during endotoxic and septic shock and is a primary mediator in the pathogenesis of the sepsis syndrome. TNF peaks in the circulation 90 min after endotoxin administration with little variation, even among species. The specific cells, tissues, or organs that produce the high circulating level of TNF in septic shock remain unknown. The most likely sources are macrophage-laden tissues such as the liver and the spleen and circulating blood leukocytes. This study evaluated whether the liver is an important source producing the TNF spike 90 min after endotoxin. To test this hypothesis, we measured the peak circulating level of TNF following an endotoxin injection in rats subjected to a two-thirds hepatectomy versus sham-operated controls. Hepatectomized rats produced 64% less TNF after endotoxin than controls (857 ± 143 pg/mL plasma vs. 2410 ± 491, respectively; p<.01). In contrast, splenectomy did not significantly alter peak TNF levels versus sham-operated controls following an endotoxin injection (1380 ± 148 pg/mL plasma vs. 1710 ± 291). Furthermore, incubation of rat blood with endotoxin for 90 min did not significantly increase TNF above controls. These experiments demonstrate an important role for the liver in producing the high circulating levels of TNF after an endotoxin injection and suggest that hepatic-specific cytokine modulation deserves study for a therapeutic benefit in septic shock.
©1996The Shock Society