Inhibition of platelet integrin GPIIbIIIa prolongs survival of discordant cardiac xenografts
Inhibition of platelet integrin GPIIbIIIa prolongs survival of discordant cardiac xenografts
复制标题
DOI：
10.1097/00007890-199607150-00001
复制
发表时间：
1996-07-15
期刊：
影响因子：
6.2
通讯作者：
Bach, FH
中科院分区：
文献类型：
--
作者：
Candinas, D;Lesnikoski, BA;Bach, FH
已知整合素GPIIbIIIa对血小板聚集体的形成至关重要，并通过纤维蛋白（原）、血管性血友病因子和玻连蛋白增强对内皮下基质的粘附。鉴于我们和其他人证明异种移植排斥反应期间广泛的血小板聚集，我们假设血小板血栓可能导致超急性排斥反应（HAR）发展期间的移植物功能障碍。以及在我们称之为延迟性异种移植排斥（DXR）的过程中，例如，如在豚鼠心脏异种移植物的补体耗尽的大鼠受体中所见，因此我们测试了特异性GPIIbIIIa拮抗剂的作用，刘易斯大鼠接受异位豚鼠心脏异种移植物，并单独用GPI 562治疗（HAR模型）或与眼镜蛇毒因子（CVF）组合（DXR型号），高（0.5 mg/kg）或低剂量在围手术期给予GPI 562（0.1 mg/kg），然后以相同剂量每天给予两次直至排斥，每天给予CVF直至排斥，在GPI 562第一次给药后和排斥反应发生时抽取血浆，检测其体外抑制ADP刺激的血小板聚集的能力，通过免疫组织学分析排斥的移植物。高剂量组的血浆完全抑制体外血小板聚集，而低剂量组的血浆仅导致部分抑制。而低剂量GPI 562不能延长移植物存活，高剂量GPI 562显示在HAR和DXR组中移植物存活的统计学显著增加。HAR的免疫组织学研究显示GPI 562对血小板聚集或活化的影响很小，对纤维蛋白沉积没有影响。然而，高剂量GPI 562和CVF的组合导致与CVF单独相比移植物内血小板聚集、P-选择素表达和白细胞浸润显著降低。总之，GPIIbIIIa拮抗剂治疗可以抑制体外血小板聚集并延长异种移植物存活，移植物内血小板微血栓形成和白细胞浸润的减少表明血小板-血小板活化在移植物内血栓形成中的重要作用。DXR期间白细胞募集的依赖机制。
The integrin GPIIbIIIa is known to be crucial to the formation of platelet aggregates and potentiates adhesion to subendothelial matrices via fibrin(ogen), von Willebrand factor, and vitronectin, Given the demonstration by us and others of widespread platelet aggregation during xenograft rejection, we hypothesized that platelet thrombi might contribute to graft dysfunction during development of hyperacute rejection (HAR), as well as during what we have termed delayed xenograft rejection (DXR), e.g., as seen in complement-depleted rat recipients of guinea pig cardiac xenografts, We therefore tested the effects of a specific GPIIbIIIa antagonist (SDZ GPI 562) during xenograft rejection.Lewis rats received heterotopic guinea pig cardiac xenografts and were treated with GPI 562 alone (HAR model) or in combination with cobra venom factor (CVF) (DXR model), A high (0.5 mg/kg) or a low dose (0.1 mg/kg) of GPI 562 was administered perioperatively and then given twice daily in the same dose until rejection, CVF was given daily until rejection, Plasma drawn after the first dose of GPI 562 and at the time of rejection was tested for the ability to inhibit ADP-stimulated platelet aggregation in vitro, Rejected grafts were analyzed by immunohistology.Plasma hom animals in the high-dose group completely inhibited platelet aggregation in vitro, whereas plasma from the low-dose group resulted in only partial inhibition, Similarly, whereas low-dose GPI 562 failed to prolong graft survival, high-dose GPI 562 showed a statistically significant increase in graft survival in both HAR and DXR groups, Immunohistologic studies of HAR showed little effect of GPI 562 on platelet aggregation or activation and no effect on fibrin deposition. However, the combination of high-dose GPI 562 and CVF resulted in a significant decrease in intragraft platelet aggregation, P-selectin expression, and leukocyte infiltration compared with CVF alone.In conclusion, GPIIbIIIa antagonist therapy can inhibit platelet aggregation in vitro and prolong xenograft survival, The diminution of intragraft platelet microthrombi formation and leukocyte infiltration suggests an important role for platelet-dependent mechanisms in leukocyte recruitment during DXR.