Enhanced endothelial tissue factor but normal thrombomodulin in endotoxin-treated rabbits.
Exposure of cultured endothelial cells to bacterial endotoxin induces an enhancement of cell procoagulant activity (PCA) and a simultaneous reduction of thrombomodulin activity (TM). We evaluated the effect of endotoxin on the expression of both endothelial PCA and TM in vivo, in rabbits. Animals were given a single i.v. injection of endotoxin (E. coli 0111:B4 LPS, W, 10-200 micrograms/kg); the thoracic aorta was harvested after 2 or 4 hours and placed in an ad hoc device to expose the endothelial surface only. Endotoxin treatment resulted in a dose-dependent increase of endothelial PCA (p < 0.001, at 100 micrograms/kg or more), which was totally dependent on factor VII and thus identified as tissue factor. In contrast, endothelial TM activity, as measured by the rate of thrombin-induced protein C activation, was similar in control and endotoxemic rabbits, even when the animals were given two injections (50 micrograms/kg, 24 h apart), or a continuous infusion (40 micrograms/kg/h during 4 hours) of endotoxin. To explore the effect of endotoxin on TM activity at the microcirculation level, we measured the extent of protein C activation in vivo, induced by a continuous infusion of low doses of thrombin (1 NIH U/kg/min for 60 min). Again, endotoxin administration was not associated with significant changes in TM-dependent protein C activation, as assessed by the anticoagulant activity present in a barium citrate plasma eluate obtained at the end of thrombin infusion. Although reduction of TM during persistent endotoxemia cannot be definitively excluded, our data support a major role of endothelial PCA in LPS-induced coagulative changes.
Semeraro
N
N
Dipartimento di Scienze Biomediche e Oncologia Umana, Università di Bari, Italy.
Triggiani
R
R
Montemurro
P
P
Cavallo
L G
LG
Colucci
M
M
D000818:Animals; D001013:Aorta, Thoracic; D001779:Blood Coagulation Factors / Q000096:biosynthesis*; D004730:Endothelium, Vascular / Q000378:metabolism*; D004731:Endotoxins / Q000494:pharmacology / Q000633:toxicity; D004789:Enzyme Activation; D005167:Factor VII / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D011486:Protein C / Q000378:metabolism; D011817:Rabbits; D012772:Shock, Septic / Q000097:blood*; D018180:Thrombomodulin / Q000096:biosynthesis*; D013925:Thromboplastin
D001779:Blood Coagulation Factors; D004731:Endotoxins; D011486:Protein C; D018180:Thrombomodulin; C053675:endothelial cell procoagulant activity; C044101:endotoxin, Escherichia coli; D005167:Factor VII; D013925:Thromboplastin