Antithrombin reduces reperfusion-induced hepatic metastasis of colon cancer cells

瞄准：检验是否反凝血酵素(在) 能阻止导致的肝的 ischemia/reperfusion (I/R ) 由禁止肿瘤的肝的转移在老鼠的 E-selectin 的坏死因素(TNF )-alpha-induced 表示。方法：肝的 I/R 被夹钳门静脉和肝的动脉的左分支在老鼠和老鼠导致。癌症房间 intrasplenically 被注射。变形小瘤的数字被依靠在 I/R 以后的白天 7。在肝的织物，浆液纤维蛋白原降级产品和肝的织物的 TNF-alpha 和 E-selectin mRNA 6-keto-PGF (1alpha ) 铺平， PGI2 的稳定的代谢物，被测量。结果：在肿瘤房间的肝的转移和在受到肝的 I/R 的动物的 TNF-alpha 和 E-selectin 的肝的织物 mRNA 层次的禁止的增加。Argatroban，一个凝血酵素禁止者，没压制任何这些变化。在并且 argatroban 禁止了 I/R-induced 凝结畸形。6-keto-PGF (1alpha ) 的肝的织物层次的 I/R-induced 增加显著地被提高由在。有消炎痛的预告的处理完全颠倒了效果在。OP-2507 的管理，稳定的 PGI2 类似于那些的模拟、显示出的效果在在这个模型。在受到肝的 I/R 的先天的在缺乏的老鼠的肝的转移显著地与在野类型的老鼠观察了那相比被增加。管理在显著地在先天的在缺乏的老鼠减少了肝的转移的数字。结论：在由通过 PGI2 的内皮生产的增加禁止 E-selectin 的 TNF-alpha-induced 表示的结肠癌房间的力量还原剂 I/R-induced 肝的转移。这些调查结果也提起可能性如果在肝肿瘤的切除术期间管理了，在力量阻止肿瘤房间的肝的转移。

AIM： To examine whether antithrombin （AT） could prevent hepatic ischemia/reperfusion （I/R）-induced hepatic metastasis by inhibiting tumor necrosis factor （TNF）-α-induced expression of E-selectin in rats. METHODS： Hepatic I/R was induced in rats and mice by clamping the left branches of the portal vein and the hepatic artery. Cancer cells were injected intrasplenically. The number of metastatic nodules was counted on day 7 after I/R. TNF-α and E-selectin mRNA in hepatic tissue, serum fibrinogen degradation products and hepatic tissue levels of 6-keto-PGF1α, a stable metabolite of PGI2, were measured. RESULTS： AT inhibited increases in hepatic metastasis of tumor cells and hepatic tissue mRNA levels of TNF-α and E-selectin in animals subjected to hepatic I/R. Argatroban, a thrombin inhibitor, did not suppress any of these changes. Both AT and argatroban inhibited I/R-induced coagulation abnormalities. I/R-induced increases of hepatic tissue levels of 6-keto-PGF1α were significantly enhanced by AT. Pretreatment with indomethacin completely reversed the effects of AT. Administration of OP-2507, a stable PGI2 analog, showed effects similar to those of AT in this model. Hepatic metastasis in congenital AT-deficient mice subjected to hepatic I/R was significantly increased compared to that observed in wild-type mice. Administration of AT significantly reduced the number of hepatic metastases in congenital AT-deficient mice. CONCLUSION： AT might reduce I/R-induced hepatic metastasis of colon cancer cells by inhibiting TNF-α-induced expression of E-selectin through an increase in the endothelial production of PGI2. These findings also raise the possibility that AT might prevent hepatic metastasis of tumor cells if administered during the resection of liver tumors.