Activated protein C preserves functional islet mass after intraportal transplantation -: A novel link between endothelial cell activation, thrombosis, inflammation, and islet cell death
Activated protein C preserves functional islet mass after intraportal transplantation -: A novel link between endothelial cell activation, thrombosis, inflammation, and islet cell death
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DOI：
10.2337/diabetes.53.11.2804
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发表时间：
2004-11-01
期刊：
影响因子：
7.7
通讯作者：
Eckhoff, DE
中科院分区：
文献类型：
--
作者：
Contreras, JL;Eckstein, C;Eckhoff, DE
临床研究表明，功能性胰岛质量的显著损失发生在围移植期。脑死亡、胰腺保存、胰岛分离、缺氧、高血糖和免疫介导的事件的有害作用导致胰岛受损。此外，最近的研究表明，胰岛由于暴露于血液和肝内内皮细胞和枯否细胞的活化而受损，导致炎症和血栓形成。活化蛋白C（APC）是一种抗凝酶，也通过直接作用于细胞发挥抗炎和抗凋亡活性。在这里，我们报告，外源性管理的重组小鼠APC（mAPC）显着减少功能性胰岛质量的损失后，门静脉移植糖尿病小鼠。给予mAPC的动物表现出更好的葡萄糖控制、更高的葡萄糖处置率和更高的精氨酸刺激的急性胰岛素释放。这些效应与移植后早期血浆胰岛素原减少、肝内纤维蛋白沉积和胰岛细胞凋亡有关。体外和体内数据表明，mAPC治疗与肝内皮细胞暴露于胰岛后促炎细胞因子释放的显著减少相关。mAPC治疗还防止了胰岛移植（PIT）固有的分离的胰岛的肝内栓塞引起的内皮细胞活化和功能障碍。本研究证明了mAPC对PIT的多种显著有益作用，并表明A-PC治疗可增强糖尿病患者PIT的治疗效果。
Clinical studies indicate that significant loss of functional islet mass occurs in the peritransplant period. Islets are injured as a result of detrimental effects of brain death, pancreas preservation, islet isolation, hypoxia, hyperglycemia, and immune-mediated events. In addition, recent studies demonstrated that islets are injured as a result of their exposure to blood and of activation of intrahepatic endothelial and Kupffer cells, resulting in inflammation and thrombosis. Activated protein C (APC) is an anticoagulant enzyme that also exerts anti-inflammatory and antiapoptotic activities by acting directly on cells. Here, we report that exogenous administration of recombinant murine APC (mAPC) significantly reduced loss of functional islet mass after intraportal transplantation in diabetic mice. Animals given mAPC exhibited better glucose control, higher glucose disposal rates, and higher arginine-stimulated acute insulin release. These effects were associated with reduced plasma proinsulin, intrahepatic fibrin deposition, and islet apoptosis early after the transplant. In vitro and in vivo data demonstrated that mAPC treatment was associated with a significant reduction of proinflammatory cytokine release after exposure of hepatic endothelial cells to islets. mAPC treatment also prevented endothelial cell activation and dysfunction elicited by intrahepatic embolization of isolated islets inherent to pancreatic islet transplantation (PIT). This study demonstrates multiple remarkable beneficial effects of mAPC for PIT and suggests that A-PC therapy may enhance the therapeutic efficacy of PIT in diabetic patients.