Combined inhibition of interleukin-1 and tumor necrosis factor in rodent endotoxemia: improved survival and organ function.
The interleukin (IL)-1 receptor antagonist (Ra) and a polyethylene glycol-linked dimer of the type I soluble receptor of tumor necrosis factor (TNF), PEG-(rsTNF-RI)2, were used to determine whether maximal protection against lethality and organ dysfunction is achieved by single or dual cytokine inhibition under rigorous conditions of rodent endotoxemia. Inhibition of IL-1 or TNF alone protected maximally against lethality when inhibitors were given simultaneously with lipopolysaccharide (LPS) under minimal lethal conditions. Combined inhibition of IL-1 and TNF was necessary to maximally protect against lethality when treatment was delayed until 7 h after LPS injection under minimal lethal conditions or when treatment was begun immediately after LPS injection under supralethal conditions. Improved survival in IL-1Ra- plus PEG-(rsTNF-RI)2-treated rats was associated with enhanced protection against renal and metabolic dysfunctions. Thus, under very severe conditions of endotoxemia, TNF and IL-1 may act independently to mediate lethality and some organ dysfunctions.
Russell
D A
DA
Synergen, Inc., Boulder, Colorado, USA.
Tucker
K K
KK
Chinookoswong
N
N
Thompson
R C
RC
Kohno
T
T
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004731:Endotoxins / Q000097:blood*; D005260:Female; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000037:antagonists & inhibitors*; D008070:Lipopolysaccharides / Q000633:toxicity*; D051381:Rats; D011917:Rats, Inbred Lew; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012795:Sialoglycoproteins / Q000008:administration & dosage*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D004731:Endotoxins; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D008070:Lipopolysaccharides; D018124:Receptors, Tumor Necrosis Factor; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha