Harada N, Okajima K, Kushimoto S, Isobe H, Tanaka K
Department of Laboratory Medicine, Kumamoto University School of Medicine, Kumamoto, Japan.
Blood. 1999 Jan 1;93(1):157-64.
We investigated whether antithrombin (AT) can reduce ischemia/reperfusion (I/R)-induced injury of rat liver by promoting prostacyclin release from endothelial cells. Although intravenous administration of AT (250 U/kg) markedly reduced hepatic injury, neither dansyl-Glu-Gly-Arg-chloromethyl ketone-treated factor Xa (DEGR-Xa), a selective inhibitor of thrombin generation, nor Trp49-modified AT, which lacks affinity for heparin, had any effect. Hepatic levels of 6-keto-PGF1, a stable prostacyclin (PGI2) metabolite, were increased significantly after I/R of the rat liver. AT significantly increased the hepatic level of 6-keto-PGF1, whereas neither DEGR-Xa nor Trp49-modified AT increased it. Hepatic tissue blood flow was markedly reduced after I/R. Although AT significantly increased the hepatic tissue blood flow after I/R, neither DEGR-Xa nor Trp49-modified AT increased the blood flow. Hepatic levels of cytokine-induced neutrophil chemoattractant (CINC) and myeloperoxidase (MPO) were significantly increased after hepatic I/R. The levels of these two indicators were reduced by AT but were unaffected by either DEGR-Xa or Trp49-modified AT. Pretreatment of animals with indomethacin (IM) completely inhibited the protective effects of AT on the I/R-induced hepatic damage and the leukocyte activation as well as the AT-induced increase in hepatic 6-keto-PGF1 levels after I/R. Iloprost, a stable analog of PGI2, exhibited effects similar to those of AT and also significantly inhibited the exacerbation of liver injury, the decrease in hepatic tissue blood flow, and the increases in hepatic CINC and MPO levels seen in rats subjected to I/R but pretreated with IM. These findings suggest that AT may prevent I/R-induced hepatic injury by increasing the hepatic levels of PGI2 through the interaction of AT with cell-surface glycosaminoglycans, thus increasing hepatic tissue blood flow and inhibiting leukocyte activation in animals subjected to I/R.
我们研究了抗凝血酶（AT）是否可通过促进内皮细胞释放前列环素，减轻大鼠肝脏缺血/再灌注（I/R）损伤。虽然静脉注射AT（250 U/kg）可显著减轻肝损伤，但凝血酶生成的选择性抑制剂丹磺酰 - 谷氨酸 - 甘氨酸 - 精氨酸 - 氯甲基酮处理的因子Xa（DEGR-Xa）以及缺乏肝素亲和力的色氨酸49修饰的AT均无此作用。大鼠肝脏I/R后，稳定的前列环素（PGI2）代谢产物6-酮 - PGF1的肝脏水平显著升高。AT可显著提高肝脏6-酮 - PGF1水平，而DEGR-Xa和色氨酸49修饰的AT均不能提高。I/R后肝组织血流量显著降低。虽然AT可显著增加I/R后的肝组织血流量，但DEGR-Xa和色氨酸49修饰的AT均不能增加血流量。肝脏I/R后，细胞因子诱导的中性粒细胞趋化因子（CINC）和髓过氧化物酶（MPO）的肝脏水平显著升高。这两个指标的水平可被AT降低，但不受DEGR-Xa或色氨酸49修饰的AT影响。用吲哚美辛（IM）预处理动物可完全抑制AT对I/R诱导的肝损伤、白细胞活化的保护作用，以及I/R后AT诱导的肝脏6-酮 - PGF1水平升高。伊洛前列素，一种稳定的PGI2类似物，表现出与AT相似的作用，也显著抑制了I/R但经IM预处理的大鼠肝脏损伤的加重、肝组织血流量的减少以及肝脏CINC和MPO水平的升高。这些发现表明，AT可能通过AT与细胞表面糖胺聚糖的相互作用增加肝脏PGI2水平，从而增加肝组织血流量并抑制I/R动物的白细胞活化，预防I/R诱导的肝损伤。
