The effect of soluble tumor necrosis factor receptor-II on endotoxin-mediated hemodynamic instability.
Tumor necrosis factor-alpha (TNF-alpha), a central mediator in the hemodynamic response to injury and infection, is a primary mediator of endotoxin-induced hemodynamic instability. Two types of naturally occurring soluble TNF receptors circulate in human experimental endotoxemia and the recombinant proteins of both have been hypothesized as potential therapeutic agents antagonizing TNF-mediated effects of endotoxemia. The administration of recombinant sTNFr-I has been previously shown to attenuate the hemodynamic collapse of lethal bacteremia. In the current study, we investigated the role of recombinant sTNFR-II at low (0.5 mg/kg) and high (2.5 mg/kg) doses as a potential therapeutic agent for the inhibition of endotoxin lipopolysaccharide (LPS)-mediated hemodynamic instability. Eighteen male Sprague-Dawley rats were anesthetized and cannulated for continuous blood pressure monitoring and cardiac output measurement by thermodilution. Groups of animals received saline, LPS (1 mg/kg), or sTNFr-II (at 0.5 or 2.5 mg/kg) 15 min prior to LPS (1 mg/kg). Hemodynamic variables (blood pressure, cardiac output, heart rate) were monitored every 15 min for 2 hr. LPS caused a 30% decrease in mean arterial pressure by 60 min, which began to recover by 120 min. sTNFr-II was unable to prevent LPS-induced hypotension at low or high dose. Serum levels of immunoreactive TNF-alpha, undetectable in control animals, were significantly increased by sTNFr-II compared to LPS alone. Serum from animals treated with high-dose sTNFr-II showed significantly less TNF cytotoxicity than those treated with low-dose sTNFr-II, indicating that high doses of sTNFr-II are required for the inhibition of the bioactivity of TNF.(ABSTRACT TRUNCATED AT 250 WORDS)
Anderson
J A
JA
Department of Surgery, University of Louisville School of Medicine, Kentucky 40292.
Knott
A W
AW
Wilson
M A
MA
Garrison
R N
RN
Sims
D E
DE
Edwards
M J
MJ
D000818:Animals; D001772:Blood Cell Count / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects; D004731:Endotoxins / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D004926:Escherichia coli; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018124:Receptors, Tumor Necrosis Factor / Q000145:classification / Q000502:physiology*; D011994:Recombinant Proteins; D012995:Solubility
D004731:Endotoxins; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins