Effects in humans of intravenously administered endotoxin on soluble cell-adhesion molecule and inflammatory markers: a model of human diseases.
1. Endotoxin, a component of the cell wall of Gram-negative bacteria, could be a predisposing mediator of many pathological disorders. The present study was undertaken to determine the effects and time-course of acute endotoxin challenge on inflammatory and cell-adhesion molecule markers shedding in the plasma as potential surrogates. 2. Six normal male subjects per group (age range 21-35 years) were injected with 4 ng/kg, i.v., reference standard Escherichia coli (0113:h10:k) endotoxin or physiological saline. 3. Plasma inflammatory markers (tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and TNF-receptor I (RI)) and cell-adhesion molecule markers (soluble L-selectin, soluble P-selectin, soluble vascular cell adhesion molecule (VCAM)-1) were determined using sensitive and specific ELISA. 4. Tumour necrosis factor-alpha increased from a basal level of 2.8 pg/mL to approximately 800 pg/mL at 90 min after endotoxin. Similarly, IL-6 peaked 2-3 h after endotoxin injection, with a rapid decline by 6-8 h, and levels returned to basal values by 24 h. 5. In contrast, TNF-RI peaked at 2 h (increasing from basal levels of 900-3300 pg/mL) with a much slower decline and without return to basal levels at 24 h (1400 pg/mL). 6. Endotoxin resulted in a rapid rise in soluble L-selectin within 1 h, which increased from a basal of 150-425 ng/mL. This rapid rise in soluble L-selectin was sustained for up to 2.5 h and then rapidly declined to basal levels by 3.5 h. 7. In contrast, plasma soluble P-selectin levels showed a delayed and progressive increase up to 8 h (increasing from a basal level of 50-95 ng/mL), with a partial decline at 24 h (80 ng/mL). 8. Similarly, soluble VCAM-1 levels showed a progressive rise up to 24 h (increasing from basal values of 600-1000 ng/mL). 9. This acute human model of endotoxin exposure demonstrated an upregulation of inflammatory stimuli leading to a short-term hyperactivation of leucocytes and a more sustained activation of platelets and endothelium. 10. This model provides a non-invasive method for studying the complex effects of endotoxin-like pathogens on different cellular events using soluble plasma surrogate markers.
Wilson
M
M
DuPont Pharmaceuticals Company, Wilmington, Delaware 19880-0400, USA.
Blum
R
R
Dandona
P
P
Mousa
S
S
D000328:Adult; D015415:Biomarkers; D001772:Blood Cell Count; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D004731:Endotoxins / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D019041:L-Selectin / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D019007:P-Selectin / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D015415:Biomarkers; D015815:Cell Adhesion Molecules; D004731:Endotoxins; D008070:Lipopolysaccharides; D019007:P-Selectin; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D019041:L-Selectin; C044101:endotoxin, Escherichia coli