Inhibition of endotoxin-induced cytokine release and neutrophil activation in humans by use of recombinant bactericidal/permeability-increasing protein.
To investigate the effects of a recombinant endotoxin-binding protein, bactericidal/permeability-increasing protein (rBPI23), on cytokine release and neutrophil activation in endotoxemia in humans, 8 volunteers were challenged twice with endotoxin and concurrently received either rBPI23 or placebo in a randomized, placebo controlled, double-blind crossover study, rBPI23 treatment significantly lowered circulating endotoxin levels (P = .02) and resulted in a significant reduction in the release of tumor necrosis factor (TNF), soluble TNF receptors p55 and p75, interleukin (IL)-6, IL-8 (P < .01 for each), and IL-10 levels (P = .02) but did not prevent the endotoxin-induced rise in body temperature. The early endotoxin-induced leukopenia was blunted (P = .08), and neutrophil degranulation, as measured by circulating levels of elastase/alpha 1-antitrypsin complexes (P = .03) and lactoferrin (P < .01), was largely prevented by rBPI23. The results of this study indicate that rBPI23 is capable of neutralizing many of the biologic effects of endotoxin in humans.
von der Möhlen
M A
MA
Center for Hemostasis, Thrombosis, Atherosclerosis, and Inflammation Research, Amsterdam, Netherlands.
Kimmings
A N
AN
Wedel
N I
NI
Mevissen
M L
ML
Jansen
J
J
Friedmann
N
N
Lorenz
T J
TJ
Nelson
B J
BJ
White
M L
ML
Bauer
R
R
D023181:Antimicrobial Cationic Peptides; D001770:Blood Bactericidal Activity; D001772:Blood Cell Count / Q000187:drug effects; D001798:Blood Proteins / Q000493:pharmacokinetics / Q000494:pharmacology*; D001831:Body Temperature / Q000187:drug effects; D018592:Cross-Over Studies; D016207:Cytokines / Q000096:biosynthesis* / Q000097:blood; D004311:Double-Blind Method; D004731:Endotoxins / Q000494:pharmacology* / Q000633:toxicity; D004926:Escherichia coli; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D007958:Leukocyte Count / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology* / Q000633:toxicity; D008297:Male; D008565:Membrane Proteins; D008657:Metabolic Clearance Rate; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D010919:Placebos; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000493:pharmacokinetics / Q000494:pharmacology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D023181:Antimicrobial Cationic Peptides; D001798:Blood Proteins; D016207:Cytokines; D004731:Endotoxins; D015850:Interleukin-6; D016209:Interleukin-8; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D010919:Placebos; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C021623:bactericidal permeability increasing protein; D016753:Interleukin-10