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.
Xuan
D
D
Department of Pharmacy Research, Hartford Hospital, Hartford, Conn 06102, USA. dxuang@harthosp.org
Nicolau
D P
DP
Nightingale
C H
CH
Quintiliani
R
R
D000818:Animals; D016470:Bacteremia / Q000150:complications*; D004195:Disease Models, Animal; D004731:Endotoxins / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism; D008297:Male; D051381:Rats; D012772:Shock, Septic / Q000503:physiopathology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000096:biosynthesis*
D004731:Endotoxins; D014409:Tumor Necrosis Factor-alpha