Gram-negative septic shock is mediated in part by endotoxin (lipopolysaccharide; LPS), and animal models have shown that blockade of even single adhesion molecules considerably improves survival. Thus interference with the adhesion cascade may provide a useful therapeutic approach in human sepsis. Young healthy men (n = 30) each received a bolus of 4 ng/kg LPS intravenously to study the effects of endotoxemia on adhesion processes in humans and to identify potential targets for pharmacologic intervention. One third of subjects received pretreatment with 1,000 mg aspirin and 1,000 mg paracetamol to study potential antiinflammatory effects of aspirin or effects of antipyresis. Circulating neutrophils dropped by -80% at 67 min after LPS, monocytes by -96% at 90 min, and lymphocytes by -85% at 240 min. L-selectin expression decreased, particularly on monocytes. Circulating (c)E-selectin levels increased by 820%, von Willebrand factor-Ag (vWF), soluble thrombomodulin, 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%. Urinary excretion of soluble adhesion molecules was negligible. Aspirin had no influence 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 surrogate marker to monitor the activation status of endothelial cells in systemic inflammation than the other markers measured. Although aspirin did not have any antiinflammatory effects in this model, paracetamol lowered the relative increase in vWF.

SNP does not decrease platelet activation during apheresis and subsequent storage, and only a minor proportion of activated (p-selectin+) platelets circulate after transfusion in men. Moreover, biotin labeling of PCs can safely be used in humans for the study of platelet recovery after transfusion, and measuring recovery at 1 hour may lead to an underestimation of the true recovery when activated platelets are transfused.

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Von Willebrand factor (VWF) and P-selectin share an identical intracellular storage compartment and transport to the cell surface. We induced degranulation of the Weibel-Palade bodies and measured circulating (c)P-selectin in plasma to test whether soluble P-selectin is present in the Weibel-Palade bodies, or if P-selectin bound to the cell membrane of endothelial cells (EC) is rapidly proteolytically cleaved in vivo. A dose of 0.3 microgram/kg of desmopressin (DDAVP) or placebo was infused over 30 min to eight healthy men in a double-blind cross-over study. Plasma levels of cP- selectin and VWF-Ag were followed for 24 h. Despite a twofold increase in VWF-Ag levels immediately after a 2 h after infusion of DDAVP, no significant change in plasma concentrations of cP-selectin were observed. In summary, degranulation of the Weibel-Palade bodies is an unlikely source of cP-selectin. Thus cP-selectin in healthy subjects is conceivably attributable to other mechanisms, such as minor degrees of platelet activation or transcription induction of an alternatively spliced P-selectin.