Am. J. Respir. Crit. Care Med., Volume 159, Number 3, March 1999, 857-863

Regulation of Adhesion Molecules during Human Endotoxemia
No Acute Effects of Aspirin

BERND JILMA, ANDREW BLANN, THOMAS PERNERSTORFER, PETRA STOHLAWETZ, HANS-GEORG EICHLER, BARBARA VONDROVEC, JEAN AMIRAL, VOLKER RICHTER, and OSWALD F. WAGNER

Department of Clinical Pharmacology, The Adhesion Research Group Elaborating Therapeutics, Clinic for Blood Group Serology and Transfusion Medicine, Department of Transfusion Medicine, University of Vienna, Vienna, Austria; Thrombosis and Vascular Biology Unit, Department of Medicine, University of Birmingham, Birmingham, United Kingdom; Department of Clinical Chemistry and Pathobiochemistry, University of Leipzig, Leipzig, Germany; and Hyphen BioMed, Research Organization, Conflans Sainte Honorine, France

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.

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