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 stu dy was undertaken to determine the effects and time-course of acute endotox in 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) endot oxin or physiological saline. 3. Plasma inflammatory markers (tumour necrosis factor (TNF)-alpha, interle ukin (IL)-6 and TNF-receptor I (RI)) and cell-adhesion molecule markers (so luble L-selectin, soluble P-selectin, soluble vascular cell adhesion molecu le (VCAM)-1) were determined using sensitive and specific ELISA. 4. Tumour necrosis factor-alpha increased from a basal level of 2.8 pg/mL t o 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 900-3 300 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, whi ch increased from a basal of 150-425 ng/mL. This rapid rise in soluble L-se lectin was sustained for up to 2.5 h and then rapidly declined to basal lev els by 3.5 h. 7. In contrast, plasma soluble P-selectin levels showed a delayed and progr essive increase up to 8 h (increasing from a basal level of 50-95 ng/mL), w ith a partial decline at 24 h (80 ng/mL). 8. Similarly, soluble VCAM-1 levels showed a progressive rise up to 24 h (i ncreasing from basal values of 600-1000 ng/mL). 9. This acute human model of endotoxin exposure demonstrated an upregulatio n of inflammatory stimuli leading to a short-term hyperactivation of leucoc ytes and a more sustained activation of platelets and endothelium. 10. This model provides a non-invasive method for studying the complex effe cts of endotoxin-like pathogens on different cellular events using soluble plasma surrogate markers.