Effects In Humans Of Intravenously Administered Endotoxin On Soluble Cell-Adhesion Molecule And Inflammatory Markers: A Model Of Human Diseases

Authors: Wilson, Mf; Blum, R; Dandona, P; Mousa, Sa

Source: Clinical and Experimental Pharmacology and Physiology, Volume 28, Numbers 5-6, May/June 2001 , pp. 376-380(5)

Publisher: Wiley-Blackwell

Abstract:

SUMMARY

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)-α, 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-α 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.

Keywords: endothelial cell; endotoxin; inflammatory markers; leucocyte; platelet; soluble adhesion molecules; tumour necrosis factor-α; tumour necrosis factor soluble receptor

Document Type: Research article

DOI: http://dx.doi.org/10.1046/j.1440-1681.2001.03463.x

Publication date: 2001-05-01

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