Thrombin and factor Xa enhance neutrophil chemoattractant production after ischemia/reperfusion in the rat liver.

Clotting proteases may affect leukocyte effector function. Activation of the coagulation cascade after ischemia/reperfusion stimulates cytokine production by activated macrophages. Cytokine-induced neutrophil chemoattractant (CINC) may also be important in the pathophysiology of liver ischemia/reperfusion injury. We investigated the effects of a selective factor Xa inhibitor, DX-9065a, on CINC expression after ischemia/reperfusion in the rat liver. Liver ischemia was induced in rats by occluding the portal vein for 30 min. DX-9065a (9 mg/kg) was injected intravenously 5 min before vascular clamping. Serum CINC concentrations were measured by enzyme-linked immunosorbent assay. Levels of CINC mRNA in the liver were determined by Northern blot analysis. We also examined in vitro CINC production by peritoneal macrophages in response to alpha-thrombin or factor Xa. Serum CINC concentrations increased and peaked 6 h after reperfusion. However, pretreatment of animals with DX-9065a resulted in significantly smaller increases in CINC after reperfusion. Pretreatment with DX-9065a also significantly reduced CINC mRNA levels in the liver after ischemia/reperfusion. In vitro CINC production by peritoneal macrophages was enhanced by alpha-thrombin, as well as factor Xa. Thrombin and factor Xa stimulate CINC production by macrophages. A selective inhibitor of factor Xa, DX-9065a, attenuates neutrophil chemoattractant production after ischemia/reperfusion injury of the rat liver.

Yamaguchi Y ，Okabe K ，Liang J ，Ohshiro H ，Ishihara K ，Uchino S ，Zhang JL ，Hidaka H ，Yamada S ，Ogawa M ... -  《JOURNAL OF SURGICAL RESEARCH》

Pretreatment with activated protein C or active human urinary thrombomodulin attenuates the production of cytokine-induced neutrophil chemoattractant following ischemia/reperfusion in rat liver.

Yamaguchi Y ，Hisama N ，Okajima K ，Uchiba M ，Murakami K ，Takahashi Y ，Yamada S ，Mori K ，Ogawa M ... -  《HEPATOLOGY》

Kupffer cell production of cytokine-induced neutrophil chemoattractant following ischemia/reperfusion injury in rats.

Hisama N ，Yamaguchi Y ，Ishiko T ，Miyanari N ，Ichiguchi O ，Goto M ，Mori K ，Watanabe K ，Kawamura K ，Tsurufuji S ，Ogawa M ... -  《HEPATOLOGY》

Urinary trypsin inhibitor reduces C-X-C chemokine production in rat liver ischemia/reperfusion.

Protease inhibitors attenuate ischemia/reperfusion injury. However, the underlying mechanisms by which protease inhibitors prevent reperfusion injury remain obscure. Neutrophils play an important role in reperfusion injury. We studied the effects of urinary trypsin inhibitor (UTI) on production of the C-X-C chemokine, cytokine-induced neutrophil chemoattractant (CINC), by Kupffer cells during ischemia/reperfusion of the liver. Liver ischemia was induced in rats by occlusion of the portal vein for 30 min. UTI (50,000 U/kg) was injected intravenously 5 min before vascular clamping. Serum CINC concentrations were measured by enzyme-linked immunosorbent assay. Levels of CINC mRNA in the liver were determined by Northern blot analysis. We also examined the inhibitory effects of UTI on in vitro CINC production by peritoneal macrophages in response to neutrophil elastase (NE). Serum CINC concentrations increased and peaked 6 h after reperfusion. However, pretreatment of animals with UTI blunted this increase in CINC and significantly reduced CINC mRNA levels in the liver after ischemia/reperfusion. UTI also decreased neutrophil accumulation in the liver 24 h after reperfusion. In vitro CINC production by Kupffer cells from rats pretreated with UTI 3 h after ischemia/reperfusion was significantly decreased compared to those from untreated animals. UTI reduced NE activity in vitro in a dose-dependent manner, and UTI significantly reduced in vitro CINC production by peritoneal macrophages stimulated with NE. UTI reduces the production of CINC by Kupffer cells stimulated with NE, attenuating ischemia/reperfusion injury of the liver.

Yamaguchi Y ，Ohshiro H ，Nagao Y ，Odawara K ，Okabe K ，Hidaka H ，Ishihara K ，Uchino S ，Furuhashi T ，Yamada S ，Mori K ，Ogawa M ... -  《JOURNAL OF SURGICAL RESEARCH》

Xanthine oxidase inhibition attenuates kupffer cell production of neutrophil chemoattractant following ischemia-reperfusion in rat liver.

Matsumura F ，Yamaguchi Y ，Goto M ，Ichiguchi O ，Akizuki E ，Matsuda T ，Okabe K ，Liang J ，Ohshiro H ，Iwamoto T ，Yamada S ，Mori K ，Ogawa M ... -  《HEPATOLOGY》