Kurata Masanao, Okajima Kenji, Kawamoto Toru, Uchiba Mitsuhiro, Ohkohchi Nobuhiro
Department of Surgery, Functional and Regulatory Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba Tennoudai 1-1-1, Tsukuba, Japan.
World J Gastroenterol. 2006 Jan 7;12(1):60-5. doi: 10.3748/wjg.v12.i1.60.
To examine whether antithrombin (AT) could prevent hepatic ischemia/reperfusion (I/R)-induced hepatic metastasis by inhibiting tumor necrosis factor (TNF)-alpha-induced expression of E-selectin in rats.
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-alpha and E-selectin mRNA in hepatic tissue, serum fibrinogen degradation products and hepatic tissue levels of 6-keto-PGF(1alpha), a stable metabolite of PGI2, were measured.
AT inhibited increases in hepatic metastasis of tumor cells and hepatic tissue mRNA levels of TNF-alpha 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-PGF(1alpha) 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.
AT might reduce I/R-induced hepatic metastasis of colon cancer cells by inhibiting TNF-alpha-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.
研究抗凝血酶（AT）是否能通过抑制肿瘤坏死因子（TNF）-α诱导的E-选择素表达来预防大鼠肝缺血/再灌注（I/R）诱导的肝转移。
通过夹闭门静脉和肝动脉的左支在大鼠和小鼠中诱导肝I/R。将癌细胞脾内注射。在I/R后第7天计数转移结节的数量。检测肝组织中TNF-α和E-选择素mRNA、血清纤维蛋白原降解产物以及肝组织中PGI2的稳定代谢产物6-酮-PGF(1α)的水平。
AT抑制了肝I/R动物中肿瘤细胞肝转移的增加以及肝组织中TNF-α和E-选择素的mRNA水平。凝血酶抑制剂阿加曲班未抑制这些变化中的任何一项。AT和阿加曲班均抑制I/R诱导的凝血异常。AT显著增强了I/R诱导的肝组织6-酮-PGF(1α)水平的升高。吲哚美辛预处理完全逆转了AT的作用。给予稳定的PGI2类似物OP-2507在该模型中显示出与AT相似的作用。与野生型小鼠相比，肝I/R的先天性AT缺陷小鼠的肝转移显著增加。给予AT显著减少了先天性AT缺陷小鼠的肝转移数量。
AT可能通过增加内皮细胞PGI2的产生来抑制TNF-α诱导的E-选择素表达，从而减少I/R诱导的结肠癌细胞肝转移。这些发现也增加了在肝肿瘤切除期间给予AT可能预防肿瘤细胞肝转移的可能性。
