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

The endotoxin-mediated tumor necrosis factor-alpha (TNF-alpha) induction wa s 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 adminis tered at various times relative to endotoxin dosing to test its anti-endoto xin activity. Results showed that endotoxin challenge initiated substantial amounts of TNF-alpha release into the rat circulaton/system leading to dea th. Atemporal pattern of TNF-alpha increases following endotoxin administra tion 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 ra ts, 5S-IgG exhibited its moderate anti-endotoxin activity by partially supp ressing the endotoxin-mediated TNF-alpha release and decreasing the overall mortality only when given before triggering of TNF-alpha induction. Howeve r, this inhibitory effect of 5S-IgG on endotoxin-mediated TNF-alpha release and the resultant protective effect against endotoxin lethality rapidly di minished when 5S-IgG was administered after the occurrence of TNF-alpha ind uction. Collectively, these results suggest that the timing of the anti-end otoxin treatment is critical in achieving its effectiveness and imply that the endotoxin levels after the onset of the cytokine cascade is of question able significance. Copyright (C) 2001 S. Karger AG, Basel.