Verstraete M, Lijnen H R
Center for Molecular and Vascular Biology, University of Leuven, Belgium.
Cardiovasc Drugs Ther. 1994 Dec;8(6):801-11. doi: 10.1007/BF00877398.
The fibrinolytic system comprises an inactive pro-enzyme, plasminogen, that is converted by plasminogen activators to the active enzyme, plasmin, that degrades fibrin. Two immunologically distinct plasminogen activators have been identified: tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA). Plasminogen activation is regulated by specific molecular interactions between its main components, as well as by controlled synthesis and release of plasminogen activator inhibitors, primarily from endothelial cells. The observed association between abnormal fibrinolysis and a tendency toward bleeding or thrombosis demonstrates the (patho)physiological importance of the fibrinolytic system. Transgenic animals are a suitable experimental model to examine the in vivo impact of fibrinolytic components in thrombosis and thrombolysis. Inactivation, by homologous recombination, of the tissue-type plasminogen activator genes in mice impairs thrombolysis in a significant manner whereas inactivation of the plasminogen activator-1 gene enhances the rate of spontaneous lysis. Despite their widespread use all currently available thrombolytic agents suffer from a number of significant limitations, including resistance to reperfusion, the occurrence of acute coronary reocclusion and bleeding complications. Therefore, the quest for thrombolytic agents with a higher thrombolytic potency, specific thrombolytic activity and/or a better fibrin-selectivity continues. Several lines of research toward improvement of thrombolytic agents are being explored, including the construction of mutants and variants of plasminogen activators, chimeric plasminogen activators, conjugates of plasminogen activators with monoclonal antibodies, or plasminogen activators from animal or bacterial origin.
纤维蛋白溶解系统由一种无活性的酶原即纤溶酶原组成，纤溶酶原被纤溶酶原激活剂转化为具有活性的酶即纤溶酶，纤溶酶可降解纤维蛋白。已鉴定出两种免疫性质不同的纤溶酶原激活剂：组织型纤溶酶原激活剂（t-PA）和尿激酶型纤溶酶原激活剂（u-PA）。纤溶酶原激活受其主要成分之间特定分子相互作用的调节，也受纤溶酶原激活剂抑制剂（主要来自内皮细胞）的受控合成和释放的调节。观察到的异常纤维蛋白溶解与出血或血栓形成倾向之间的关联证明了纤维蛋白溶解系统的（病理）生理重要性。转基因动物是研究纤维蛋白溶解成分在血栓形成和溶栓过程中体内影响的合适实验模型。通过同源重组使小鼠组织型纤溶酶原激活剂基因失活会显著损害溶栓作用，而纤溶酶原激活剂-1基因失活则会提高自发溶解的速率。尽管目前所有可用的溶栓剂都被广泛使用，但它们都存在一些重大局限性，包括对再灌注的抵抗、急性冠状动脉再闭塞的发生以及出血并发症。因此，人们仍在继续寻找具有更高溶栓效力、特异性溶栓活性和/或更好纤维蛋白选择性的溶栓剂。目前正在探索几条改进溶栓剂的研究路线，包括构建纤溶酶原激活剂的突变体和变体、嵌合纤溶酶原激活剂、纤溶酶原激活剂与单克隆抗体的缀合物，或来自动物或细菌来源的纤溶酶原激活剂。
