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Evaluation of antiinflammatory and antiadhesive effects of heparins in human endotoxemia.

Abstract：

OBJECTIVE:Cytokines and adhesion molecules have a decisive role in the development of early inflammatory response as well as the late sequelae of sepsis. Because L-selectin-deficient mice are protected from lethal endotoxemia, blockade of L-selectin may provide a useful therapeutic option in human sepsis. Heparin has immunomodulatory properties and effectively inhibits L- and P-selectin binding in vitro. We therefore investigated whether clinically applied doses of unfractionated or low-molecular-weight heparin affect early inflammatory response in human endotoxemia. DESIGN:The study was randomized, double-blinded, placebo-controlled, in three parallel groups consisting of 30 healthy male volunteers. SETTING:University medical center. INTERVENTIONS:All subjects received a 2-ng/kg intravenous bolus of lipopolysaccharide and 10 mins later unfractionated heparin, low-molecular-weight heparin, or placebo as bolus primed continuous infusion for 6 hrs. MEASUREMENTS AND MAIN RESULTS:Lipopolysaccharide infusion induced similar increases of tumor necrosis factor-alpha, interleukin-6, interleukin-8, C-reactive protein, and soluble E-selectin levels in all treatment groups. CD11b expression increased by approximately 400%, but L-selectin decreased by 41% in the placebo arm 6 hrs after lipopolysaccharide infusion. Interestingly, both heparins (in particular unfractionated heparin) decreased L-selectin down-regulation as compared with placebo. Similarly, the decrease in lymphocyte counts was significantly less in the unfractionated heparin group during the first 24 hrs (p <.05 vs. placebo) CONCLUSIONS:Heparins displayed little effects on cytokine production and endothelial cell activation in endotoxemia. Of note, however, unfractionated heparin reduced L-selectin down-regulation and lymphocytopenia. These could present novel mechanisms of action of unfractionated heparin.

journal_name

Crit Care Med

journal_title

Critical care medicine

authors

Derhaschnig U,Pernerstorfer T,Knechtelsdorfer M,Hollenstein U,Panzer S,Jilma B

doi

10.1097/01.CCM.0000059441.70680.DC

subject

Has Abstract

pub_date

2003-04-01 00:00:00

pages

1108-12

issue

eissn

0090-3493

issn

1530-0293

journal_volume

pub_type

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Evaluation of antiinflammatory and antiadhesive effects of heparins in human endotoxemia.