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.

• Authors: Ulla Derhaschnig, Thomas Pernerstorfer, Marteen Knechtelsdorfer, Ursula Hollenstein, Simon Panzer, Bernd Jilma
• Journal: Critical care medicine (Crit Care Med) Vol. 31 Issue 4 Pg. 1108-12 (Apr 2003) ISSN: 0090-3493 [Print] United States
• PMID: 12682480 (Publication Type: Clinical Trial, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Antithrombins
• CD11b Antigen
• Cytokines
• Heparin, Low-Molecular-Weight
• P-Selectin
• L-Selectin
• Heparin

Topics

• Adult
• Anti-Inflammatory Agents (therapeutic use)
• Antithrombins (analysis)
• Blood Cell Count
• CD11b Antigen (blood)
• Cytokines (blood)
• Double-Blind Method
• Endotoxemia (blood, drug therapy, physiopathology)
• Heparin (therapeutic use)
• Heparin, Low-Molecular-Weight (therapeutic use)
• Humans
• L-Selectin (blood, drug effects)
• Leukocytes (physiology)
• Male
• P-Selectin (blood)
• Platelet Adhesiveness