Inhibition of factor Xa suppresses the expression of tissue factor in human monocytes and lipopolysaccharide-induced endotoxemia in rats.
BACKGROUND
Activated factor X (FXa) is involved in hemostasis, thrombogenesis, inflammation, and cellular immune response. Tissue factor (TF) is an initiator of blood coagulation. We investigated whether FXa induces TF expression in human peripheral monocytes and whether treatment with FXa inhibitor reduces TF expression in an experimental model of rat endotoxemia.


METHODS
Human peripheral mononuclear cells were used to determine TF expression induced by FXa. Experimental rat endotoxemia was induced by intravenous bolus injection of lipopolysaccharide (LPS). A specific FXa inhibitor, DX-9065a, was administered subcutaneously immediately after LPS injection.


RESULTS
FXa induced TF expression in monocytes without intervention of thrombin and the expression was suppressed by FXa inhibitor. In the experimental model of rat endotoxemia, TF and TF mRNA expression levels in the liver were reduced by DX-9065a. Moreover, administration of DX-9065a suppressed the rise in plasma concentrations of thrombin-antithrombin III complex (TAT) and monocyte chemoattractant protein-1 (MCP-1).


CONCLUSIONS
Our results indicated that FXa can induce TF expression in human peripheral monocytes and that inhibition of FXa reduces TF expression in the liver of rat endotoxemia. These results suggest that FXa is an important factor for TF expression in sepsis.
Akahane
K
K
Department of Surgery I, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, Japan.
Okamoto
K
K
Kikuchi
M
M
Todoroki
H
H
Higure
A
A
Ohuchida
T
T
Kitahara
K
K
Takeda
S
S
Itoh
H
H
Ohsato
K
K
D000818:Animals; D018932:Chemokine CCL2 / Q000097:blood; D019446:Endotoxemia / Q000378:metabolism*; D015951:Factor Xa / Q000502:physiology; D065427:Factor Xa Inhibitors; D006801:Humans; D007150:Immunohistochemistry; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000378:metabolism; D008297:Male; D009000:Monocytes / Q000378:metabolism*; D009281:Naphthalenes / Q000494:pharmacology*; D011422:Propionates / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D013925:Thromboplastin / Q000096:biosynthesis* / Q000235:genetics
C086910:(2S)-2-(4-(((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy)phenyl)-3-(7-amidino-2-naphtyl)propanoic acid; D018932:Chemokine CCL2; D065427:Factor Xa Inhibitors; D008070:Lipopolysaccharides; D009281:Naphthalenes; D011422:Propionates; D012333:RNA, Messenger; D013925:Thromboplastin; D015951:Factor Xa