Hypoxia primes endotoxin-induced tissue factor expression in human monocytes and endothelial cells by a PAF-dependent mechanism.
Tissue factor (TF) is a glycoprotein which acts as a trigger of the coagulation cascade. TF expression may be induced at the surface of monocytes and endothelial cells by several stimuli including bacterial endotoxin (LPS) and cytokines (IL 1 beta, TNF alpha) and there is a large body of evidence for the involvement of hypoxia as a primaring factor in the process leading to thrombosis. To define the molecular basis underlying this phenomenon, we evaluated the relative role of platelet activating factor (PAF). PAF primed human monocytes and human umbilical vein endothelial cells (HUVEC) for TF expression following exposure to E coli LPS but was unable to enhance the induction of TF expression by IL 1 beta. The priming effect of PAF with regard to LPS occurred in a time- and dose-dependent manner and was inhibited by the PAF receptor antagonist SR 27417. When HUVEC or monocytes were exposed to an hypoxic environment, a significant rise in LPS-induced TF expression was observed. Hypoxia had no effect on IL 1-induced TF expression. The enhanced LPS-induced TF expression in both cell types was mediated by PAF as indicated by the inhibition obtained with SR 27417, added during hypoxia. Although the importance of hypoxia in the etiology of venous thrombosis has been acknowledged for a long time, evaluation of the relative importance of PAF in the process leading to thrombus formation is still lacking. Stasis-induced thrombosis performed in the rabbit jugular vein was enhanced in a dose-dependent manner by the prior i.v. administration of LPS (0.05 to 100 micrograms/ kg, i.v.). SR 27417 administered simultaneously with LPS prevented thrombus formation with an ED50 value of 0.1 +/- 0.04 mg/kg. These results therefore show that hypoxia promotes LPS-induced TF expression in HUVEC and human monocytes through a PAF-dependent mechanism in vitro and in vivo.
Haemobiology Research Department, Sanofi Recherche, Toulouse, France.
J M
JM
Herbert
D
D
Corseaux
A
A
Lale
A
A
Bernat
D000818:Animals; D002478:Cells, Cultured; D004731:Endotoxins / Q000494:pharmacology*; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D007375:Interleukin-1 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D010972:Platelet Activating Factor / Q000494:pharmacology*; D011817:Rabbits; D013844:Thiazoles / Q000494:pharmacology; D013924:Thrombophlebitis / Q000378:metabolism; D013925:Thromboplastin / Q000187:drug effects / Q000378:metabolism* / Q000494:pharmacology; D014470:Umbilical Cord
D004731:Endotoxins; D007375:Interleukin-1; D008070:Lipopolysaccharides; D010972:Platelet Activating Factor; D013844:Thiazoles; D013925:Thromboplastin; C071317:Foropafant