Treatment with recombinant human tumor necrosis factor-alpha protects rats against the lethality, hypotension, and hypothermia of gram-negative sepsis

H. Richard Alexander, Brett Sheppard, J. Christian Jensen, Howard N. Langstein, Carolyn M. Buresh, David Venzon, Elijah C. Walker, Douglas L. Fraker, Mark C. Stovroff, Jeffrey A. Norton

Research output: Contribution to journalArticle

125 Citations (Scopus)

Abstract

Tumor necrosis factor (TNF) is a peptide secreted by macrophages in response to endotoxin that can produce many of the changes seen in septic shock. After cecal ligation and puncture (CLP) rats gradually develop tachycardia, hypotension, tachypnea, and hypothermia. At 5 h post-CLP, rats have a peak in serum levels of endotoxin and 60% of rats have blood cultures that grow Gram-negative rods (Escherichia coli and Klebsiella pneumonia). At 20 h post-CLP all rats develop positive blood cultures. Serum levels of TNF are not reproducibly measurable in rats following CLP. Rats undergoing CLP have a 50-80% mortality with deaths usually occurring 24-72 h postinjury. Repetitive (twice daily × 6 d) i.p. injection of sublethal doses of recombinant human TNF-alpha (100 μg/kg) to rats undergoing CLP 1 d after the treatment period resulted in a significant reduction in mortality compared to control rats previously unexposed to rTNF (P <0.03). Animals treated with rTNF had no hypotension or hypothermia after CLP and regained normal food intake faster than control rats. 12 h after CLP the gene expression for manganous Superoxide dismutase (MnSOD), an inducible mitochondrial metalloenzyme responsible for cellular resistance to injury from toxic reactive oxygen species, was higher in livers of rats treated with rTNF suggesting that the TNF treatment augmented expression of this protective enzyme. Unlike MnSOD, expression of the gene for copper-zinc SOD was not affected by CLP or rTNF treatment. The results suggest that prior treatment with recombinant TNF can ameliorate the lethality, hypotension, hypothermia, and anorexia of Gram-negative sepsis in rats and that the mechanism may be related to enhanced hepatic expression of the gene for MnSOD. Repeated administration of recombinant TNF may be a strategy to minimize mortality and morbidity of Gram-negative sepsis.

Original languageEnglish (US)
Pages (from-to)34-39
Number of pages6
JournalJournal of Clinical Investigation
Volume88
Issue number1
StatePublished - 1991
Externally publishedYes

Fingerprint

Hypothermia
Hypotension
Sepsis
Punctures
Tumor Necrosis Factor-alpha
Ligation
Therapeutics
Superoxide Dismutase
Gene Expression
Endotoxins
Mortality
human TNF protein
Tachypnea
Poisons
Liver
Klebsiella pneumoniae
Anorexia
Septic Shock
Serum
Tachycardia

Keywords

  • Cachectin
  • Cytokine
  • Tolerance

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Richard Alexander, H., Sheppard, B., Christian Jensen, J., Langstein, H. N., Buresh, C. M., Venzon, D., ... Norton, J. A. (1991). Treatment with recombinant human tumor necrosis factor-alpha protects rats against the lethality, hypotension, and hypothermia of gram-negative sepsis. Journal of Clinical Investigation, 88(1), 34-39.

Treatment with recombinant human tumor necrosis factor-alpha protects rats against the lethality, hypotension, and hypothermia of gram-negative sepsis. / Richard Alexander, H.; Sheppard, Brett; Christian Jensen, J.; Langstein, Howard N.; Buresh, Carolyn M.; Venzon, David; Walker, Elijah C.; Fraker, Douglas L.; Stovroff, Mark C.; Norton, Jeffrey A.

In: Journal of Clinical Investigation, Vol. 88, No. 1, 1991, p. 34-39.

Research output: Contribution to journalArticle

Richard Alexander, H, Sheppard, B, Christian Jensen, J, Langstein, HN, Buresh, CM, Venzon, D, Walker, EC, Fraker, DL, Stovroff, MC & Norton, JA 1991, 'Treatment with recombinant human tumor necrosis factor-alpha protects rats against the lethality, hypotension, and hypothermia of gram-negative sepsis', Journal of Clinical Investigation, vol. 88, no. 1, pp. 34-39.
Richard Alexander, H. ; Sheppard, Brett ; Christian Jensen, J. ; Langstein, Howard N. ; Buresh, Carolyn M. ; Venzon, David ; Walker, Elijah C. ; Fraker, Douglas L. ; Stovroff, Mark C. ; Norton, Jeffrey A. / Treatment with recombinant human tumor necrosis factor-alpha protects rats against the lethality, hypotension, and hypothermia of gram-negative sepsis. In: Journal of Clinical Investigation. 1991 ; Vol. 88, No. 1. pp. 34-39.
@article{b1a010c92e1740fcb5b47abc37286db5,
title = "Treatment with recombinant human tumor necrosis factor-alpha protects rats against the lethality, hypotension, and hypothermia of gram-negative sepsis",
abstract = "Tumor necrosis factor (TNF) is a peptide secreted by macrophages in response to endotoxin that can produce many of the changes seen in septic shock. After cecal ligation and puncture (CLP) rats gradually develop tachycardia, hypotension, tachypnea, and hypothermia. At 5 h post-CLP, rats have a peak in serum levels of endotoxin and 60{\%} of rats have blood cultures that grow Gram-negative rods (Escherichia coli and Klebsiella pneumonia). At 20 h post-CLP all rats develop positive blood cultures. Serum levels of TNF are not reproducibly measurable in rats following CLP. Rats undergoing CLP have a 50-80{\%} mortality with deaths usually occurring 24-72 h postinjury. Repetitive (twice daily × 6 d) i.p. injection of sublethal doses of recombinant human TNF-alpha (100 μg/kg) to rats undergoing CLP 1 d after the treatment period resulted in a significant reduction in mortality compared to control rats previously unexposed to rTNF (P <0.03). Animals treated with rTNF had no hypotension or hypothermia after CLP and regained normal food intake faster than control rats. 12 h after CLP the gene expression for manganous Superoxide dismutase (MnSOD), an inducible mitochondrial metalloenzyme responsible for cellular resistance to injury from toxic reactive oxygen species, was higher in livers of rats treated with rTNF suggesting that the TNF treatment augmented expression of this protective enzyme. Unlike MnSOD, expression of the gene for copper-zinc SOD was not affected by CLP or rTNF treatment. The results suggest that prior treatment with recombinant TNF can ameliorate the lethality, hypotension, hypothermia, and anorexia of Gram-negative sepsis in rats and that the mechanism may be related to enhanced hepatic expression of the gene for MnSOD. Repeated administration of recombinant TNF may be a strategy to minimize mortality and morbidity of Gram-negative sepsis.",
keywords = "Cachectin, Cytokine, Tolerance",
author = "{Richard Alexander}, H. and Brett Sheppard and {Christian Jensen}, J. and Langstein, {Howard N.} and Buresh, {Carolyn M.} and David Venzon and Walker, {Elijah C.} and Fraker, {Douglas L.} and Stovroff, {Mark C.} and Norton, {Jeffrey A.}",
year = "1991",
language = "English (US)",
volume = "88",
pages = "34--39",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "1",

}

TY - JOUR

T1 - Treatment with recombinant human tumor necrosis factor-alpha protects rats against the lethality, hypotension, and hypothermia of gram-negative sepsis

AU - Richard Alexander, H.

AU - Sheppard, Brett

AU - Christian Jensen, J.

AU - Langstein, Howard N.

AU - Buresh, Carolyn M.

AU - Venzon, David

AU - Walker, Elijah C.

AU - Fraker, Douglas L.

AU - Stovroff, Mark C.

AU - Norton, Jeffrey A.

PY - 1991

Y1 - 1991

N2 - Tumor necrosis factor (TNF) is a peptide secreted by macrophages in response to endotoxin that can produce many of the changes seen in septic shock. After cecal ligation and puncture (CLP) rats gradually develop tachycardia, hypotension, tachypnea, and hypothermia. At 5 h post-CLP, rats have a peak in serum levels of endotoxin and 60% of rats have blood cultures that grow Gram-negative rods (Escherichia coli and Klebsiella pneumonia). At 20 h post-CLP all rats develop positive blood cultures. Serum levels of TNF are not reproducibly measurable in rats following CLP. Rats undergoing CLP have a 50-80% mortality with deaths usually occurring 24-72 h postinjury. Repetitive (twice daily × 6 d) i.p. injection of sublethal doses of recombinant human TNF-alpha (100 μg/kg) to rats undergoing CLP 1 d after the treatment period resulted in a significant reduction in mortality compared to control rats previously unexposed to rTNF (P <0.03). Animals treated with rTNF had no hypotension or hypothermia after CLP and regained normal food intake faster than control rats. 12 h after CLP the gene expression for manganous Superoxide dismutase (MnSOD), an inducible mitochondrial metalloenzyme responsible for cellular resistance to injury from toxic reactive oxygen species, was higher in livers of rats treated with rTNF suggesting that the TNF treatment augmented expression of this protective enzyme. Unlike MnSOD, expression of the gene for copper-zinc SOD was not affected by CLP or rTNF treatment. The results suggest that prior treatment with recombinant TNF can ameliorate the lethality, hypotension, hypothermia, and anorexia of Gram-negative sepsis in rats and that the mechanism may be related to enhanced hepatic expression of the gene for MnSOD. Repeated administration of recombinant TNF may be a strategy to minimize mortality and morbidity of Gram-negative sepsis.

AB - Tumor necrosis factor (TNF) is a peptide secreted by macrophages in response to endotoxin that can produce many of the changes seen in septic shock. After cecal ligation and puncture (CLP) rats gradually develop tachycardia, hypotension, tachypnea, and hypothermia. At 5 h post-CLP, rats have a peak in serum levels of endotoxin and 60% of rats have blood cultures that grow Gram-negative rods (Escherichia coli and Klebsiella pneumonia). At 20 h post-CLP all rats develop positive blood cultures. Serum levels of TNF are not reproducibly measurable in rats following CLP. Rats undergoing CLP have a 50-80% mortality with deaths usually occurring 24-72 h postinjury. Repetitive (twice daily × 6 d) i.p. injection of sublethal doses of recombinant human TNF-alpha (100 μg/kg) to rats undergoing CLP 1 d after the treatment period resulted in a significant reduction in mortality compared to control rats previously unexposed to rTNF (P <0.03). Animals treated with rTNF had no hypotension or hypothermia after CLP and regained normal food intake faster than control rats. 12 h after CLP the gene expression for manganous Superoxide dismutase (MnSOD), an inducible mitochondrial metalloenzyme responsible for cellular resistance to injury from toxic reactive oxygen species, was higher in livers of rats treated with rTNF suggesting that the TNF treatment augmented expression of this protective enzyme. Unlike MnSOD, expression of the gene for copper-zinc SOD was not affected by CLP or rTNF treatment. The results suggest that prior treatment with recombinant TNF can ameliorate the lethality, hypotension, hypothermia, and anorexia of Gram-negative sepsis in rats and that the mechanism may be related to enhanced hepatic expression of the gene for MnSOD. Repeated administration of recombinant TNF may be a strategy to minimize mortality and morbidity of Gram-negative sepsis.

KW - Cachectin

KW - Cytokine

KW - Tolerance

UR - http://www.scopus.com/inward/record.url?scp=0025893127&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0025893127&partnerID=8YFLogxK

M3 - Article

C2 - 2056127

AN - SCOPUS:0025893127

VL - 88

SP - 34

EP - 39

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 1

ER -