Dose-related inflammatory effects of intravenous endotoxin in humans: evaluation of a new clinical lot of Escherichia coli O:113 endotoxin.
The administration of reference endotoxin (Escherichia coli O:113, Lot EC-5) to humans has been an important means to study inflammation in vivo; however, the supply of Lot EC-5 is depleted. A new lot of reference endotoxin (Clinical Center reference endotoxin [CCRE]), derived from the original bulk material extracted from E. coli O:113, was processed. The effects of 0-, 1-, 2-, and 4-ng/kg doses of intravenous CCRE and EC-5 were studied in 20 male subjects. CCRE resulted in dose-related increases in symptoms, temperature (P=. 016), total leukocyte count (P=.014), tumor necrosis factor-alpha (P=.004), interleukin (IL)-1 receptor antagonist (P=.004), IL-6 (P=. 005), IL-8 (P=.011), cortisol (P<.05), and C-reactive protein (P=. 04). These responses were attenuated (all P<.012) in subjects given Lot EC-5 (4 ng/kg) in comparison with those in subjects given CCRE, showing that, over several years, EC-5 had lost potency. Thus, in healthy subjects, the magnitude of exposure to CCRE results in a graded dose response of major components of innate immunity.
Suffredini
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AF
Critical Care Medicine Department, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA. anthony_suffredini@nih.gov
Hochstein
H D
HD
McMahon
F G
FG
D000328:Adult; D016207:Cytokines / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins / Q000008:administration & dosage* / Q000633:toxicity; D005069:Evaluation Studies as Topic; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007249:Inflammation / Q000276:immunology* / Q000473:pathology*; D007275:Injections, Intravenous; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D009316:National Institutes of Health (U.S.); D012015:Reference Standards; D014481:United States
D016207:Cytokines; D004731:Endotoxins; C044101:endotoxin, Escherichia coli; D006854:Hydrocortisone