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


METHODS
The study was randomized, double-blinded, placebo-controlled, in three parallel groups consisting of 30 healthy male volunteers.


METHODS
University medical center.


METHODS
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.


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.
Derhaschnig
Ulla
U
Service de Réanimation Médicale, Hôpital Pitié-Salpêtrière, Hôpital Bichat, Paris, France.
Pernerstorfer
Thomas
T
Knechtelsdorfer
Marteen
M
Hollenstein
Ursula
U
Panzer
Simon
S
Jilma
Bernd
B
D000328:Adult; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D000991:Antithrombins / Q000032:analysis; D001772:Blood Cell Count; D039481:CD11b Antigen / Q000097:blood; D016207:Cytokines / Q000097:blood; D004311:Double-Blind Method; D019446:Endotoxemia / Q000097:blood* / Q000188:drug therapy / Q000503:physiopathology; D006493:Heparin / Q000627:therapeutic use*; D006495:Heparin, Low-Molecular-Weight / Q000627:therapeutic use; D006801:Humans; D019041:L-Selectin / Q000097:blood / Q000187:drug effects; D007962:Leukocytes / Q000502:physiology; D008297:Male; D019007:P-Selectin / Q000097:blood; D010973:Platelet Adhesiveness
D000893:Anti-Inflammatory Agents; D000991:Antithrombins; D039481:CD11b Antigen; D016207:Cytokines; D006495:Heparin, Low-Molecular-Weight; D019007:P-Selectin; D019041:L-Selectin; D006493:Heparin