Single-dose tumor necrosis factor protection against endotoxin-induced shock and tissue injury in rats.
Tumor necrosis factor (TNF), a macrophage product released in response to endotoxin and other stimuli, has been shown to be a central mediator of endotoxin or septic shock. However, its highly conserved and wide-ranging physiological effects suggest that it may also be an essential cytokine in the host defense against acute bacterial infection or sepsis. A single nontoxic dose of human recombinant TNF administered intravenously 24 h prior to a lethal infusion of Escherichia coli lipopolysaccharide (LPS) completely prevented acute LPS-induced hypotension, ameliorated tissue injury in the lungs and liver, and improved survival in male Fisher 344 rats. The protective effects of TNF were dose dependent and required a 24-h pretreatment interval. After the infusion of LPS, animals in both groups (TNF-treated animals and saline-pretreated controls) initially appeared acutely ill and had a similar severe metabolic acidosis, indicating that TNF did not inactivate or prevent the toxic effects of LPS. Twelve hours after the administration of TNF, the gene for manganous superoxide dismutase, a mitochondrial enzyme which scavenges toxic reactive oxygen species and is induced during conditions which generate a free radical stress, was expressed in liver tissue, suggesting that the induction of manganous superoxide dismutase may be an important in vivo protective mechanism against cellular injury during lethal endotoxemia.
Surgical Metabolism Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
H R
HR
Alexander
G M
GM
Doherty
M I
MI
Block
P J
PJ
Kragel
J C
JC
Jensen
H N
HN
Langstein
E
E
Walker
J A
JA
Norton
D000818:Animals; D015152:Blotting, Northern; D004790:Enzyme Induction; D015870:Gene Expression; D008070:Lipopolysaccharides / Q000633:toxicity*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D012772:Shock, Septic / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D013482:Superoxide Dismutase / Q000235:genetics*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use*
D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D013482:Superoxide Dismutase