The evaluation of thrombomodulin activity in porcine to human xenotransplantation.
The evaluation of thrombomodulin activity in porcine to human xenotransplantation.
复制标题
猪与人异种移植中血栓调节蛋白活性的评价。
DOI：
10.1016/s0041-1345(96)00192-3
复制
发表时间：
1997
影响因子：
0.9
通讯作者：
Platt,JL
中科院分区：
文献类型：
--
作者：
Lawson,JH;Daniels,LJ;Platt,JL
成功的异种移植的局限性之一是缺乏与人类有密切遗传关系的动物（即灵长类动物），或者当使用不同物种（如猪）作为器官供体时观察到的积极排斥反应。然而，基因工程的最新进展已经使人们有可能对猪进行改造，从而避免导致超急性排斥反应的免疫过程。当不协调器官的超急性排斥反应得以避免时，异种移植物会发生延迟性排斥反应，其特征是移植器官内的微血管血栓形成和纤维蛋白沉积。这种血栓形成过程可能部分反映了与跨物种不相容性相关的止血调节基本要素之间的内在缺陷，从而导致移植失败。这促使我们研究灵长类动物和猪之间凝血过程的元素是如何调节的。止血失调的一个潜在领域是来源于移植器官的细胞蛋白与来源于宿主的血浆相蛋白的相互作用。这种相互作用发生在抗凝剂途径中，该途径受猪内皮细胞上表达的血栓调节蛋白及其与血浆来源的（人）凝血酶和蛋白C的结合调节。我们已经评估了猪血栓调节蛋白激活人蛋白C的能力，因为它会发生在猪到人异种移植的血管系统中。对单核吞噬细胞的作用活化蛋白C在单核细胞上形成时，可以结合这些细胞并阻断细胞内钙信号传导。[16]由此可见，血栓调节蛋白及其对蛋白C活化的控制代表了凝血系统、炎症途径和炎症细胞活化之间的重要界面。此外，这种细胞结合受体/辅因子蛋白还代表了器官移植背景下供体细胞结合蛋白和血浆相宿主蛋白之间的分子界面。我们已经研究了猪血栓调节蛋白是否会调节人蛋白C的活化，使用一种新的异种移植模型，即用纯化的人和猪血浆蛋白灌注新鲜分离的猪血管。血栓调节蛋白是一种跨膜糖蛋白，表达于血管内皮细胞、血小板6和单核细胞的表面。血栓调节蛋白通过凝血酶依赖性激活蛋白C，在抗凝途径的启动中发挥核心作用。8一旦活化蛋白C（aPC）形成，它迅速反馈到血液凝固途径，降解促凝血辅因子Va和VIIIa，从而进一步阻断促凝血蛋白酶的产生。这种途径在提供天然抗凝方面的生物学重要性通过在具有蛋白C、“蛋白S”或因子Va突变缺陷的患者中血管血栓形成的发生而得到强调，所述突变使得活化的辅因子对aPC失活具有抗性。“. 13
NE OF THE limitations of successful xenotransplantation has been either the lack of available animals with close genetic relation to humans (ie, primates), or the aggressive rejection response observed when disparate species such as pigs are used as organ donors.’However, recent advances in genetic engineering have made it possible to modify the swine in such a way that the immunological process leading to hyperacute rejection can be averted.* When hyperacute rejection of discordant organs is averted the xenograft becomes subject to a delayed rejection process characterized by microvascular thrombosis and fibrin deposition within the transplanted organ.’This thrombotic process could in part reflect an intrinsic defect among basic elements of hemostatic regulation related to cross-species incompatibility leading to graft failure. This led us to investigate how elements of the blood clotting process are regulated between primates and swine. One potential area of hemostatic dysregulation is the interaction of cellular proteins derived from the transplanted organ and plasma phase proteins derived from the host. Such interactions occur in the anticoagulant pathway which is regulated by thrombomodulin expressed on pig endothelial cells and its binding with plasma derived (human) thrombin and protein C. We have evaluated the ability of porcine thrombomodulin to activate human protein C as it would occur in the vasculature of a pig to human xenotransplant. vation on mononuclear phagocytes.‘43” Activated protein C, when formed on mononuclear cells, can bind to these cells and block intracellular calcium signaling. 16 In this light, thrombomodulin and its control of protein C activation, represents an important interface between the blood clotting system, inflammatory pathways, and the activation of inflammatory cells. Furthermore, this cell bound receptor/cofactor protein also represents a molecular interface between donor cell bound proteins and plasma phase host proteins in the setting of organ transplantation. We have investigated whether porcine thrombomodulin would regulate the activation of human protein C using a novel xenotransplant model of perfusing freshly isolated porcine blood vessels with purified human and porcine plasma proteins.Thrombomodulin is a transmembrane glycoprotein which is expressed on the surface of vascular endothelial cells, 4.5 platelets6 and monocytes.’Thrombomodulin plays a central role in the initiation of anticoagulant pathways via thrombin dependent activation of protein C. 8 Once activated protein C (aPC) is formed, it rapidly feeds back into the blood coagulation pathways, degrading the procoagulant cofactors Va and VIIIa, thus blocking further procoagulant protease production.” The biological importance of this pathway in providing natural anticoagulation is underscored by the occurrence of vascular thrombosis in patients with deficiencies of protein C,‘” protein S,” or mutations in factor Va which render the activated cofactor resistant to aPC inactivation.“. 13