A synthetic selective inhibitor of factor Xa, DX-9065a, reduces monocyte chemoattractant protein-1 expression after ischemia-reperfusion injury in rat liver.
Activated factor X (FXa) is a trypsinlike serine protease involved in the cascade of blood coagulation. The monocyte chemoattractant protein-1 (MCP-1) may be important in the pathophysiology of liver ischemia-reperfusion injury. We investigated the effects of a selective FXa inhibitor, DX-9065a, on MCP-1 expression after ischemia-reperfusion in the rat liver. Liver ischemia was induced in rats by occluding the portal vein for 30 min. DX-9065a was injected intravenously 5 min before vascular clamping. Serum concentrations of MCP-1 were measured by enzyme-linked immunosorbent assay. The levels of MCP-1 mRNA in the liver after reperfusion were determined by northern blot analysis. In vitro MCP-1 production by peritoneal macrophages in response to alpha-thrombin was examined. Serum concentrations of MCP-1 increased and peaked at 6 hr after reperfusion. However, pretreatment of animals with DX-9065a resulted in significantly smaller increases in the serum concentration of MCP-1 after reperfusion in a dose-dependent manner. Pretreatment with DX-9065a significantly reduced MCP-1 mRNA levels in the liver after ischemia-reperfusion. In vitro MCP-1 production by peritoneal macrophages was enhanced by alpha-thrombin. In addition, DX-9065a significantly reduced tissue factor mRNA levels in peripheral monocytes after ischemia-reperfusion, compared to untreated animals. In conclusion, a selective inhibitor of FXa, DX-9065a, limited MCP-1 production after ischemia-reperfusion of the rat liver.
Yamaguchi
Y
Y
Department of Surgery II, Kumamoto University Medical School, Japan.
Okabe
K
K
Liang
J
J
Matsumura
F
F
Ohshiro
H
H
Ishihara
K
K
Matsuda
T
T
Takeya
M
M
Kuratsu
J I
JI
Mori
K
K
Yamada
S
S
Ogawa
M
M
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D015152:Blotting, Northern; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000097:blood*; D004797:Enzyme-Linked Immunosorbent Assay; D065427:Factor Xa Inhibitors; D007728:Kupffer Cells / Q000378:metabolism; D008099:Liver / Q000098:blood supply* / Q000737:chemistry; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology*; D011422:Propionates / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000097:blood*
C086910:(2S)-2-(4-(((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy)phenyl)-3-(7-amidino-2-naphtyl)propanoic acid; D000925:Anticoagulants; D018932:Chemokine CCL2; D065427:Factor Xa Inhibitors; D009281:Naphthalenes; D011422:Propionates; D012333:RNA, Messenger