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Abstract
Based on the hypothesis that tumor necrosis factor (TNF) causes the lethality of gram-negative
sepsis and previous work of tolerance to the lethal effects of TNF induced by repetitive
exposure to sublethal intraperitoneal doses of human recombinant (r) TNF, we studied
the protective role of a single sublethal intravenous dose of either rTNF (100 μg/kg)
or recombinant interleukin-1 (rIL-1; 105 units/kg) or both before a subsequent lethal intravenous dose of rTNF (800 to 1000
μg/kg) in ![Math Eq]()
mice. Mice were treated with a single intravenous dose of saline, rTNF, rIL-1 or
both cytokines and challenged within 2 hours to 10 days with a lethal dose of rTNF.
Mice treated with rTNF showed significant protection against the lethal effects of
TNF when the treatment dose was given only 2 hours before the lethal dose, but maximal
protection required a 24-hour interval and lasted as long as 8 days. The treatment
dose of rTNF was toxic, and it resulted in occasional treatment deaths. Mice treated
with rIL-1 showed maximal protection when treatment was given only 2 hours before
challenge and protection lasted for 8 days. No toxicity was apparent secondary to
IL-1 treatment. The combination of rIL-1 and rTNF was not as effective as either cytokine
alone. The results suggest that rTNF or rIL-1 may be clinically useful in the prevention
and treatment of sepsis lethality by the induction of tolerance to the lethal effects
of TNF. The more promising cytokine appears to be rIL-1 because it has less toxicity
and more rapid induction of full therapeutic effectiveness.
mice. Mice were treated with a single intravenous dose of saline, rTNF, rIL-1 or
both cytokines and challenged within 2 hours to 10 days with a lethal dose of rTNF.
Mice treated with rTNF showed significant protection against the lethal effects of
TNF when the treatment dose was given only 2 hours before the lethal dose, but maximal
protection required a 24-hour interval and lasted as long as 8 days. The treatment
dose of rTNF was toxic, and it resulted in occasional treatment deaths. Mice treated
with rIL-1 showed maximal protection when treatment was given only 2 hours before
challenge and protection lasted for 8 days. No toxicity was apparent secondary to
IL-1 treatment. The combination of rIL-1 and rTNF was not as effective as either cytokine
alone. The results suggest that rTNF or rIL-1 may be clinically useful in the prevention
and treatment of sepsis lethality by the induction of tolerance to the lethal effects
of TNF. The more promising cytokine appears to be rIL-1 because it has less toxicity
and more rapid induction of full therapeutic effectiveness.To read this article in full you will need to make a payment
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Article info
Publication history
Accepted:
July 13,
1990
Footnotes
☆Presented in part at the 45th meeting of the American College of Surgeons, Atlanta, Ga., October 17, 1989.
Identification
Copyright
© 1991 Published by Elsevier Inc.
