Potential attenuation of fibrinolysis by growth factors released from platelets and their pharmacologic implications.
Potential attenuation of fibrinolysis by growth factors released from platelets and their pharmacologic implications.
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血小板释放的生长因子可能减弱纤溶作用及其药理学意义。
DOI：
10.1016/0002-9149(89)90016-7
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发表时间：
1989
期刊：
影响因子：
--
通讯作者：
Sobel,BE
中科院分区：
文献类型：
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作者：
Fujii,S;Lucore,CL;Hopkins,WE;Billadello,JJ;Sobel,BE
速效组织型纤溶酶原激活剂（t-PA）抑制剂浓度的增加会减弱药物施用的纤溶系统激活剂（例如t-PA）的纤溶活性。因此，推测来自肝脏的抑制剂的合成和加工的增加，导致血浆中抑制剂的浓度增加，或者来自正在溶解的血栓附近的内皮细胞的抑制剂的浓度增加，导致局部浓度增加，可能导致药物诱导的溶栓失败或早期再闭塞。由于血小板富含转化生长因子β和表皮生长因子样活性，因此人们认为体内激活的血小板释放的生长因子可以通过刺激其在肝脏中的形成以及血栓附近的内皮细胞的局部释放来介导血浆中抑制剂的增加。如果是这样，通过同时防止血小板生长因子释放，纤维蛋白溶解可能会更加有效。转化生长因子β（血小板的主要成分）会以特定且剂量依赖性的方式增加人肝癌细胞中t-PA抑制剂信使核糖核酸（mRNA）的浓度。 5 ng/ml 时效果达到峰值，6 小时内增加 10 倍。释放到条件培养基中的抑制剂蛋白也增加。短暂暴露 30 分钟即可诱导抑制剂 mRNA 增加。放线菌酮是一种蛋白质合成抑制剂，但没有抑制作用。其作用机制与表皮生长因子不同，此前实验室已证明其可增加抑制剂 mRNA。此外，这两个因素具有协同作用。血小板裂解物引起的效果与纯化的生长因子的效果相似。因此，体内冠状动脉血栓附近的血小板被激活时释放的血小板相关生长因子可能会增加内皮细胞释放t-PA抑制剂（局部减弱纤维蛋白溶解），增加肝脏合成和释放抑制剂（导致循环中抑制剂增加），从而增强梗死相关冠状动脉的早期血栓再闭塞。
Increased concentrations of the fast-acting tissuetype plasminogen activator (t-PA) inhibitor attenuate the fibrinolytic activity of pharmacologically administered activators of the fibrinolytic system such as t-PA. Accordingly, it was hypothesized that augmentation of synthesis and elaboration of inhibitor from the liver, leading to increased concentrations of inhibitor in plasma, or from endothelial cells in the vicinity of thrombi undergoing lysis, leading to increased concentrations locally, may contribute to failure of pharmacologically induced thrombolysis or to early reocclusion. Because platelets are rich in transforming growth factor beta and epidermal growth factor-like activity, it was thought that release of growth factors from platelets activated in vivo could mediate increases of the inhibitor in plasma by stimulating its formation in the liver and its local release from endothelial cells in the vicinity of thrombi. If so, fibrinolysis might be rendered more effective by concomitant prevention of platelet growth factor release.Transforming growth factor beta, a major constituent of platelets, increased concentrations of the t-PA inhibitor messenger ribonucleic acid (mRNA) in human hepatoma cells in a specific and dose-dependent manner. A peak effect was seen with 5 ng/ ml and a 10-fold increase in 6 hours. Release of inhibitor protein into conditioned media increased as well. Induction of the inhibitor mRNA increase was elicited by exposure as brief as 30 minutes. Cycloheximide, an inhibitor of protein synthesis, was not inhibitory. The mechanisms responsible differed from those seen with epidermal growth factor, shown previously in the laboratory to increase inhibitor mRNA. In addition, the 2 factors were synergistic. Platelet lysates elicited effects simulating those of the purified growth factors. Thus, platelet-associated growth factors released when platelets are activated in the vicinity of coronary thrombi in vivo may augment the release of t-PA inhibitor by endothelial cells (attenuating fibrinolysis locally), increase synthesis and release of inhibitor by the liver (leading to increased inhibitor in the circulation) and thereby potentiate early thrombotic reocclusion of infarct-related coronary arteries.