Effect of high-dose dexamethasone on endothelial haemostatic gene expression and neutrophil adhesion.
Glucocorticoid usage especially at high doses is complicated by adverse outcomes such as thrombotic events or acceleration of inflammatory response in conditions like myeloma and osteonecrosis. The mechanism(s) through which high-dose dexamethasone (HDDEXA) causes vascular injury remains unclear. We hypothesized that HDDEXA sensitizes endothelial cells (EC) to the effect of inflammatory mediators and modulates endothelial haemostatic gene expression and leukocyte adhesion. Human umbilical vein endothelial cells (HUVECs) were grown in the absence or presence of HDDEXA and were also tested in the presence or absence of tumor necrosis factor-alpha (TNF-alpha), lipopolysaccharide (LPS) or thrombin. mRNA and protein expression were measured and the functional consequences of HDDEXA preconditioning on cell adhesion molecules (CAM) were determined by agonist-mediated leukocyte adhesion assay. Treatment with HDDEXA resulted in an increased induction of CAM, tissue factor and von Willebrand factor, while down-regulating thrombomodulin and urokinase. HDDEXA alone had no effect on adhesion but resulted in enhanced TNF-alpha- and LPS-mediated adhesion of neutrophils. Together, these findings suggest that HDDEXA sensitizes HUVEC to the effect of inflammatory mediators and induces a pro-adhesive environment in primary EC. This finding is of importance when glucocorticoid usage is required at therapeutic high doses in patients with or without thrombotic risk factors.
Kerachian
Mohammad Amin
MA
Department of Human Genetics, McGill University Health Center, Montreal, Canada.
Cournoyer
Denis
D
Harvey
Edward J
EJ
Chow
Terry Y
TY
Neagoe
Paul-Eduard
PE
Sirois
Martin G
MG
Séguin
Chantal
C
D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003907:Dexamethasone / Q000008:administration & dosage / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology*; D020869:Gene Expression Profiling; D005938:Glucocorticoids / Q000009:adverse effects*; D006487:Hemostasis / Q000235:genetics*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D013917:Thrombin / Q000494:pharmacology; D018180:Thrombomodulin / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D014841:von Willebrand Factor / Q000378:metabolism
D015815:Cell Adhesion Molecules; D005938:Glucocorticoids; D008070:Lipopolysaccharides; D018180:Thrombomodulin; D014409:Tumor Necrosis Factor-alpha; D014841:von Willebrand Factor; D003907:Dexamethasone; D013917:Thrombin; D014568:Urokinase-Type Plasminogen Activator