1 Department of Hepatobiliary, Pancreas and Transplant Surgery, Kyoto University, Kyoto, Japan. 2 Institute for Laboratory Animal Science and Experimental Surgery, RWTH-Aachen University, Aachen, Germany. 3 Address correspondence to: Shintaro Yagi, M.D., Ph.D., Department of Hepatobiliary, Pancreas and Transplant Surgery, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
Transplantation. 2014 Mar 27;97(6):618-25. doi: 10.1097/TP.0000000000000025.
Liver transplant outcomes using grafts donated after cardiac death (DCD) remain poor.
We investigated the effects of ex vivo reconditioning of DCD grafts with venous systemic oxygen persufflation using nitric oxide gas (VSOP-NO) in rat liver transplants. Orthotopic liver transplants were performed in Lewis rats, using DCD grafts prepared using static cold storage alone (group-control) or reconditioning using VSOP-NO during cold storage (group-VSOP-NO). Experiment I: In a 30-min warm ischemia model, graft damage and hepatic expression of inflammatory cytokines, endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), and endothelin-1 (ET-1) were examined, and histologic analysis was performed 2, 6, 24, and 72 hr after transplantation. Experiment II: In a 60-min warm ischemia model, grafts were evaluated 2 hr after transplantation (6 rats/group), and survival was assessed (7 rats/group).
Experiment I: Group-VSOP-NO had lower alanine aminotransferase (ALT) (P<0.001), hyaluronic acid (P<0.05), and malondialdehyde (MDA) (P<0.001), hepatic interleukin-6 expression (IL-6) (P<0.05), and hepatic tumor necrosis factor-alpha (TNF-α) expression (P<0.001). Hepatic eNOS expression (P<0.001) was upregulated, whereas hepatic iNOS (P<0.01) and ET-1 (P<0.001) expressions were downregulated. The damage of hepatocyte and sinusoidal endothelial cells (SECs) were lower in group-VSOP-NO.Experiment II: VSOP-NO decreased ET-1 and 8-hydroxy-2'deoxyguanosine (8-OHdG) expression and improved survival after transplantation by 71.4% (P<0.01).
These results suggest that VSOP-NO effectively reconditions warm ischemia-damaged grafts, presumably by decreasing ET-1 upregulation and oxidative damage.
使用心脏死亡后捐献的供体进行肝移植的结果仍然很差。
我们研究了使用一氧化氮气体（VSOP-NO）进行静脉全身氧灌注对大鼠肝移植中心脏死亡（DCD）供体进行体外再灌注的效果。使用单纯静态冷保存（对照组）或冷保存期间使用 VSOP-NO 进行再灌注（VSOP-NO 组）制备 DCD 移植物，在 Lewis 大鼠中进行原位肝移植。实验 I：在 30 分钟热缺血模型中，检查供体损伤和肝内炎症细胞因子、内皮型一氧化氮合酶（eNOS）、诱导型一氧化氮合酶（iNOS）和内皮素-1（ET-1）的表达，并在移植后 2、6、24 和 72 小时进行组织学分析。实验 II：在 60 分钟热缺血模型中，在移植后 2 小时评估移植物（每组 6 只大鼠），并评估存活情况（每组 7 只大鼠）。
实验 I：VSOP-NO 组丙氨酸氨基转移酶（ALT）（P<0.001）、透明质酸（P<0.05）和丙二醛（MDA）（P<0.001）、肝内白细胞介素-6 表达（IL-6）（P<0.05）和肝肿瘤坏死因子-α表达（TNF-α）（P<0.001）较低。肝 eNOS 表达上调（P<0.001），而肝 iNOS（P<0.01）和 ET-1（P<0.001）表达下调。VSOP-NO 组肝细胞和窦内皮细胞（SECs）损伤较低。实验 II：VSOP-NO 降低 ET-1 和 8-羟基-2'-脱氧鸟苷（8-OHdG）表达，移植后存活率提高 71.4%（P<0.01）。
这些结果表明，VSOP-NO 通过降低 ET-1 的上调和氧化损伤，有效地对热缺血损伤的供体进行再灌注。
