Regulation of Adhesion Molecules during Human Endotoxemia

Abstract

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.

Systemic inflammation increases shear stress‐induced platelet plug formation measured by the PFA‐100

“…Thirty healthy men aged 19±35 years were included in this study after obtaining written informed consent. Our LPS model has been described in detail previously (Jilma et al, 1999). All volunteers were free of medication for at least 3 weeks prior to the first study day.…”

Heparin Blunts Endotoxin-Induced Coagulation Activation

“…Concomitant with the onset of infusion, participants of the trial received 500 mg of paracetamol (Paracetamol Genericon Pharma), which alleviates subjective symptoms without compromising the host response. 15 Thirty minutes thereafter, all subjects received a bolus of LPS 2 ng/kg IV (national reference endotoxin, Escherichia coli; USP Convention Inc, Rockville, Md). Ten minutes after LPS infusion, study subjects in the UFH group received 80 IU/kg (Heparin Immuno, Immuno Ag) followed by a continuous UFH infusion at a rate of 18 IU ⅐ kg Ϫ1 ⅐ h Ϫ1 for 6 hours.…”

Relationship of peripheral blood neutrophil to lymphocyteratio and irritable bowel syndrome

“…Due to the fact that the physiological response of the circulating leukocytes against stress causes an increase in the neutrophil count and a decrease in the lymphocyte count, the ratio of these two subgroups is used as a precise indicator of inflammation (18,19). Changes occur in the ratio of circulating leukocytes during inflammatory response.…”

“…There are studies related to antibiotic usage in IBS patients such as excessive bacterial growth, subclinical inflammation, and rifaximin (18)(19)(20)(21).…”