Tumor necrosis factor and endotoxin induce similar metabolic responses in human beings.
After injury, infection, or major operations a number of predictable metabolic responses occur. It has been proposed that the cytokine tumor necrosis factor (TNF)/cachectin is a primary mediator of these host responses. To test this hypothesis, we studied 16 tumor-bearing humans with normal renal and hepatic function, who received 24-hour continuous intravenous infusions of escalating doses of recombinant TNF (4 to 636/micrograms/m2/24 h). Serial measurements were made of vital signs and plasma concentrations of TNF, interleukin-1, adrenocorticotropic hormone, cortisol, iron, glucose, and C-reactive protein. Low doses of TNF had minimal metabolic effects, but infusions of greater than or equal to 545 micrograms/m2/24 hr (n = 8) resulted in fever, pituitary, and stress hormone release and acute phase changes. These alterations were compared with the changes that occurred in healthy humans (n = 13) receiving intravenous bolus injections of Escherichia coli endotoxin (4 ng/kg). TNF infusion in doses greater than or equal to 545 micrograms/m2/24 hr produced peak plasma TNF concentrations and metabolic responses that were similar to those after endotoxin injection. Interleukin-1 concentrations remained basal after TNF or endotoxin administration. TNF may represent the primary afferent signal that initiates many of the metabolic responses associated with sepsis and endotoxemia.
Michie
H R
HR
Laboratory for Surgical Metabolism and Nutrition, Brigham and Women's Hospital, Boston, MA 02115.
Spriggs
D R
DR
Manogue
K R
KR
Sherman
M L
ML
Revhaug
A
A
O'Dwyer
S T
ST
Arthur
K
K
Dinarello
C A
CA
Cerami
A
A
Wolff
S M
SM
D000209:Acute-Phase Proteins / Q000097:blood; D000210:Acute-Phase Reaction / Q000097:blood*; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000328:Adult; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D004731:Endotoxins / Q000494:pharmacology*; D004926:Escherichia coli; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007249:Inflammation / Q000097:blood*; D008297:Male; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*
D000209:Acute-Phase Proteins; D004731:Endotoxins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone