Regulation of adhesion molecules during human endotoxemia - No acute effects of aspirin

Gram-negative septic shock is mediated in part by endotoxin (lipopolysaccha ride; LPS), and animal models have shown that blockade of even single adhes ion molecules considerably improves survival. Thus interference with the ad hesion cascade may provide a useful therapeutic approach in human sepsis. Y oung healthy men (n = 30) each received a bolus of 4 ng/kg LPS intravenousl y to study the effects of endotoxemia on adhesion processes in humans and t o identify potential targets for pharmacologic intervention. One third of s ubjects received pretreatment with 1,000 mg aspirin and 1,000 mg paracetamo l to study potential antiinflammatory effects of aspirin or effects of anti pyresis. Circulating neutrophils dropped by -80% at 67 min after LPS, monoc ytes by -96% at 90 min, and lymphocytes by -85% at 240 min. L-selectin expr ession decreased, particularly on monocytes. Circulating (c)E-selectin leve ls increased by 820%, von Willebrand factor-Ag (VWF), soluble thrombomoduli n, circulating (c)P-selectin, circulating intercellular adhesion molecule-1 (cICAM-1), and circulating vascular cell adhesion molecule-1 (cVCAM-1) by a mean of 65 to 98% (p < 0.001 for all), but cL-selectin by only 15%. Urina ry excretion of soluble adhesion molecules was negligible. Aspirin had no i nfluence on the LPS-induced changes of adhesion parameters, but paracetamol blunted the relative increase in vWF while having no effects on the other parameters measured. The consistent, profound, and early upregulation of cE -selectin during endotoxemia indicates that cE-selectin may be a better sur rogate marker to monitor the activation status of endothelial cells in syst emic inflammation than the other markers measured. Although aspirin did not have any antiinflammatory effects in this model, paracetamol lowered the r elative increase in vWF.