Reduction of hepatic ischemia/reperfusion injury by a soluble P-selectin glycoprotein ligand-1
Reduction of hepatic ischemia/reperfusion injury by a soluble P-selectin glycoprotein ligand-1
复制标题
DOI：
10.1097/00000658-199806000-00006
复制
发表时间：
1998-06-01
影响因子：
9
通讯作者：
Busuttil, RW
中科院分区：
文献类型：
--
作者：
Dulkanchainun, TS;Goss, JA;Busuttil, RW
目的作者的目标是确定可溶性 P-选择素糖蛋白配体-1 (PSGL-1) 在大鼠体内热缺血和离体冷缺血模型中特异性结合和阻断 P-和 E-选择素的效果。作者还试图确定选择素阻断对同基因大鼠原位肝移植模型中同种移植物存活的影响。 背景数据摘要缺血/再灌注 (I/R) 损伤是肝移植后移植物功能不良的主要因素，可能深刻影响早期移植物功能和晚期变化。据推测，I/R损伤导致P-选择素上调，然后在肝脏再灌注5分钟内迅速转移至内皮细胞表面，启动导致多形核中性粒细胞束缚至血管内膜的步骤。白细胞局部产生白细胞介素-1、肿瘤坏死因子-α或两者，诱导内皮上P-选择素表达，并继续级联事件，从而增加细胞粘附和器官浸润。方法为了直接检查选择素在热肝I/R损伤模型中的作用，在实验时通过门静脉给予100μg PSGL-1或盐水。 完全肝流入闭塞。在威斯康星大学 (UW) 溶液中 4 摄氏度储存 6 小时后，使用离体灌注大鼠肝脏评估 PSGL-1 在冷缺血中的作用，无论在储存前是否滴注 PSGL-1。为了评估选择素阻断对肝移植存活的影响，在 UW 溶液中冷缺血储存 24 小时后，在近交系雄性 Sprague-Dawley 大鼠之间进行同基因原位肝移植。另一组动物在储存前和移植肝脏再灌注前通过门静脉接受两剂100μg PSGL-1。在第 7 天评估受体存活率，并使用 Kaplan-Meier 乘积极限估计方法对时间依赖性受体存活事件进行单变量计算。结果在体内温大鼠肝缺血模型中，灌注 PSGL-1 可以提供相当大的保护，免受 I/R 损伤，转氨酶释放减少、组织学肝细胞损伤减少和中性粒细胞受到抑制证明了这一点。 与对照相比，渗透率（p < 0.05）。当冷藏的肝脏再灌注时，PSGL-1 降低了肝细胞转氨酶释放的程度，减少了中性粒细胞浸润，并减少了组织学肝细胞损伤（与仅使用 UW 的对照相比，p < 0.05）。再灌注时，用 PSGL-1 治疗的肝脏表现出门静脉血流量和胆汁产生增加（与仅使用 UW 的对照组相比，p < 0.05）。此外，接受储存在补充有 PSGL-1 的 UW 溶液中的同种肝脏移植物的大鼠中有 90% 存活了 7 天，而移植的同基因肝脏仅储存在 UW 中的大鼠存活了 7 天 (p < 0.05)。 结论 选择素在肝脏 I/R 损伤中发挥着重要作用。在温暖和寒冷的大鼠肝脏缺血模型中，早期调节 P-选择素及其配体之间的相互作用可减少肝细胞损伤、中性粒细胞粘附以及随后的迁移。此外，在缺血保存前和移植前使用 PSGL-1 可预防肝损伤，肝同种移植物存活率显着增加已证明。这些发现具有重要的临床意义：在 I/R 损伤期间早期抑制同种异体抗原独立机制可能会影响同种异体肝移植物的短期和长期存活。
ObjectiveThe authors' goal was to determine the effects of specific binding and blockade of P-and E-selectins by a soluble P-selectin glycoprotein ligand-1 (PSGL-1) in rat models of hepatic in vivo warm ischemia and ex vivo cold ischemia. The authors also sought to determine the effect of selectin blockade on isograft survival in a syngeneic rat orthotopic liver transplant model.Summary Background DataIschemia/reperfusion (I/R) injury is a major factor in poor graft function after liver transplantation, which may profoundly influence early graft function and late changes. it is hypothesized that I/R injury leads to the upregulation of P-selectin, which is then rapidly translocated to endothelial cell surfaces within 5 minutes of reperfusion of the liver, initiating steps leading to tethering of polymorphonuclear neutrophil leukocytes to the vascular intima. Local production by leukocytes of interleukin-1, tumor necrosis factor-alpha or both induces P-selectin expression on the endothelium and continues the cascade of events, which increases cell adherence and infiltration of the organ.MethodsTo examine directly the effects of selectins in a warm hepatic I/R injury model, 100 mu g of PSGL-1 or saline was given through the portal vein at the time of total hepatic inflow occlusion. The effects of PSGL-1 in cold ischemia were assessed using an isolated perfused rat liver after 6 hours of 4 degrees C storage in University of Wisconsin (UW) solution, with or without the instillation of PSGL-1 before the storage. To evaluate the effect of selectin blockade on liver transplant survival, syngeneic orthotopic liver transplants were performed between inbred male Sprague-Dawley rats after 24 hours of cold ischemic storage in UW solution. A separate group of animals received two doses of 100 mu g of PSGL-1 through the portal vein before storage and before reperfusion of the transplanted liver. Recipient survival was assessed at 7 days, and the Kaplan-Meier product limit estimate method was used for univariate calculations of time-dependent recipient survival events.ResultsIn an in vivo warm rat liver ischemia model, perfusion with PSGL-1 afforded considerable protection from I/R injury, as demonstrated by decreased transaminase release, reduced histologic hepatocyte damage, and suppressed neutrophil infiltration, versus controls (p < 0.05). When cold stored livers were reperfused, PSGL-1 reduced the degree of hepatocyte transaminase release, reduced neutrophil infiltration, and decreased histologic hepatocyte damage (p < 0.05 vs. UW-only controls). On reperfusion, livers treated with PSGL-1 demonstrated increased portal vein blood flow and bile production (p < 0.05 vs. UW-only controls). in addition, 90% of the rats receiving liver isografts stored in UW solution supplemented with PSGL-1 survived 7 days versus 50% of those whose transplanted syngeneic livers had been stored in UW alone (p < 0.05).ConclusionsSelectins play an important role in I/R injury of the liver. Early modulation of the interaction between P-selectin and its ligand decreases hepatocyte injury, neutrophil adhesion, and subsequent migration in both warm and cold rat liver ischemia models. In addition, the use of PSGL-1 before ischemic storage and before transplantation prevents hepatic injury, as documented by a significant increase in liver isograft survival. These findings have important clinical ramifications: early inhibition of alloantigen-independent mechanisms during the I/R damage may influence both short-and long-term survival of liver allografts.