Circulating tumor necrosis factor-alpha production during the progression of rat endotoxic sepsis.

The endotoxin-mediated tumor necrosis factor-alpha (TNF-alpha) induction was investigated in a rat endotoxin septic shock model. Rats were challenged intravenously with lethal doses of endotoxin. Circulating endotoxin and TNF-alpha concentrations were measured over various times following endotoxin administration. A derivative of human immunoglobulin G, 5S-IgG, was administered at various times relative to endotoxin dosing to test its anti-endotoxin activity. Results showed that endotoxin challenge initiated substantial amounts of TNF-alpha release into the rat circulatory system leading to death. A temporal pattern of TNF-alpha increases following endotoxin administration was observed; the rat plasma TNF-alpha level rapidly increased 60 min after endotoxin injection, peaked around 120 min and returned to low levels by 240 min. A rapid clearance pattern of endotoxin was also observed in rats. 5S-IgG exhibited its moderate anti-endotoxin activity by partially suppressing the endotoxin-mediated TNF-alpha release and decreasing the overall mortality only when given before triggering of TNF-alpha induction. However, this inhibitory effect of 5S-IgG on endotoxin-mediated TNF-alpha release and the resultant protective effect against endotoxin lethality rapidly diminished when 5S-IgG was administered after the occurrence of TNF-alpha induction. Collectively, these results suggest that the timing of the anti-endotoxin treatment is critical in achieving its effectiveness and imply that the endotoxin levels after the onset of the cytokine cascade is of questionable significance. Copyright 2001 S. Karger AG, Basel