Antithrombin reduces ischemia/reperfusion injury of rat liver by increasing the hepatic level of prostacyclin
Antithrombin reduces ischemia/reperfusion injury of rat liver by increasing the hepatic level of prostacyclin
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DOI：
10.1182/blood.v93.1.157.401k08_157_164
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发表时间：
1999-01-01
期刊：
影响因子：
20.3
通讯作者：
Tanaka, K
中科院分区：
文献类型：
--
作者：
Harada, N;Okajima, K;Tanaka, K
我们研究了抗凝血酶（AT）是否可以通过促进内皮细胞释放前列环素来减轻大鼠肝脏缺血/再灌注（I/R）损伤。尽管静脉注射AT（250 U/kg）可显著减轻肝损伤，但无论是经丹磺酰-Glu-Gly-Arg-氯甲基酮处理的凝血因子Xa（DEGR-Xa）（凝血酶生成的选择性抑制剂），还是经Trp（49）修饰的AT（对肝素缺乏亲和力），均无任何作用。大鼠肝脏I/R后，肝脏中稳定的前列环素（PGI（2））代谢产物6-酮-PGF（1 α）水平显著升高。AT显著增加肝脏6-keto-PGF（1 α）水平，而DEGR-Xa和Trp（49）修饰的AT均不增加肝脏6-keto-PGF（1 α）水平。尽管AT显著增加了I/R后的肝组织血流量，但DEGR-Xa和Trp（49）修饰的AT均未增加血流量。肝I/R后，肝脏中性粒细胞趋化因子（CINC）和髓过氧化物酶（MPO）水平显著升高。这两个指标的水平被AT降低，但不受DEGR-Xa或Trp（49）修饰的AT的影响。用吲哚美辛（IM）预处理动物，可完全抑制AT对I/R引起的肝损伤和白细胞活化的保护作用，以及AT引起的I/R后肝脏6-keto-PGF（1 α）水平升高。伊洛前列素是一种稳定的PGI类似物（2），表现出与AT相似的作用，并且还显著抑制了I/R大鼠中观察到的肝损伤加重、肝组织血流量减少以及肝CINC和MPO水平升高，但在I/R大鼠中进行了IM预处理。这些发现表明，AT可以通过AT与细胞表面糖胺聚糖的相互作用增加肝脏PGI（2）水平，从而增加肝组织血流量并抑制I/R动物中白细胞活化，从而预防I/R诱导的肝损伤。(C)1999年，美国血液学会。
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 Trp(49)-modified AT, which lacks affinity for heparin, had any effect. Hepatic levels of 6-keto-PGF(1 alpha), a stable prostacyclin (PGI(2)) metabolite, were increased significantly after I/R of the rat liver. AT significantly increased the hepatic level of 6-keto-PGF(1 alpha), whereas neither DEGR-Xa nor Trp(49)-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 Trp(49)-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 Trp(49)-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-PGF(1 alpha) levels after I/R. Iloprost, a stable analog of PGI(2), 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 PGI(2) 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. (C) 1999 by The American Society of Hematology.