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; howe ver, 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 ma le subjects. CCRE resulted in dose-related increases in symptoms, temperatu re (P = .016), total leukocyte count (P = .014), tumor necrosis factor-alph a (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, o ver several years, EC-5 had lost potency. Thus, in healthy subjects, the ma gnitude of exposure to CCRE results in a graded dose response of major comp onents of innate immunity.