Normothermic Machine Perfusion Protects Against Liver Ischemia-Reperfusion Injury During Reduced-Size Liver Transplantation in Pigs

Abstract

BackgroundNormothermic machine perfusion (NMP) preservation is superior to cold preservation during reduced-size liver transplantation (RSLT) in pigs. However, the mechanism of this protective effect has not been explained. We aimed to compare the effects of NMP preservation with that of cold preservation (CS) in protecting against ischemia-reperfusion injury (IRI) during RSLT in pigs.Material/MethodsTwenty-four healthy Bama miniature pigs were randomized into 2 groups: 1) the NMP group in which donor livers harvested without warm ischemia time and cardiac activity were connected to the NMP system to reduce liver size under normothermic conditions, and 2) the CS group in which donor livers harvested without warm ischemia time and cardiac activity were perfused using the University of Wisconsin (UW) solution and then preserved in the 0–4°C UW solution to reduce liver size under cold conditions. Livers were then transplanted without veno-venous bypass. Amounts of bile secretion for the NMP groups were recorded hourly. The serological indices were measured. Expressions of cytochrome C, caspase 3, and NF-κB p65 in liver tissue were observed.ResultsThe levels of bile secretions were gradually diminished from 16.50±2.66 mL/h before splitting to 6.35±1.24 mL/h after splitting. With the exception of TNF-α on postoperative day 2, overall, levels of TNF-α, IL-1, IL-6, and MDA were significantly lower in the NMP group versus CS group for all 5 days postoperatively. Finally, cytochrome C, caspase 3, and NF-κB p65 expressions were all significantly suppressed in the NMP group as compared with the CS group.ConclusionsMP preservation is superior to cold preservation in protecting against liver IRI during RSLT in pigs.

Restoring Mitochondrial Function While Avoiding Redox Stress: The Key to Preventing Ischemia/Reperfusion Injury in Machine Perfused Liver Grafts?

“…The expression was significantly reduced in the human livers preserved with NMP compared to the SCS group. Moreover, NMP may reduce the expression levels of cytochrome c and caspase-3, which was observed in the study of Zhang in porcine livers [48]. This suggests a decrease in apoptotic cell death as induced by IRI.…”

“…Several studies in liver grafts have already shown a benefit of NMP on IRI, even though complete prevention of IRI cannot be expected. Zhang et al [48] conducted a study with reduced-size porcine livers and applied NMP prior to transplantation. Compared to the control group (SCS), serum levels of the proinflammatory cytokines TNFα and IL-6 were significantly decreased in the NMP group post transplantation.…”

Organ Preservation in Liver Transplantation

“…The authors found a significant difference in intraoperative bleeding, ALT and AST levels, and proinflammatory cytokines, which supported the use of NMP. 84 A Canadian single-center study comparing the use of NMP versus standard static CS produced no such promising results, however. Ten liver grafts (4 DCD and 6 DBD) were assessed and nine were transplanted.…”

机械灌注在肝移植中的研究进展

“…常温机械灌注通过在保持常温(35~38°C)的环境中提 供氧气和必需的底物，模拟肝脏的生理状态，维持正常的新 陈代谢。大量动物实验 [40][41][42] 证实了 NMP 在保存 DCD 供肝 方面的优越性。此外，NMP 可通过检测肝脏代谢指标(胆汁 产量，乳酸，肝酶释放水平等)对供肝质量进行评估。2013 年，op den Dries 等 [43] 首次对 4 例弃用的人供肝进行 6h 的 HMP，灌注液中的生化指标提示，乳酸水平下降至正常值， 胆汁分泌正常，肝脏的缺血再灌注损伤减轻，功能改善，且 灌注 6h 前后组织学无损伤表现。最近报道的一项突破性研究， Eshmuminov 等 [44] 对 10 例废弃人供肝采用 NMP 保存 1 周后， 其中 6 例供肝任能分泌胆汁，合成凝血因子，生成 ATP，且 肝脏结构保持完整。2016 年，Perera 等 [45] 报道了首例采用 NMP 保存边缘供肝肝移植的临床试验，受者术后恢复顺利， 随访 15 个月，未出现胆道并发症。随后，Ravikumar 等 [46] 报 道了采用 NMP 保存供肝肝移植的一期临床试验结果，NMP 组包括 16 例 DBD 供肝和 4 例 DCD 供肝，30 天移植物存活 率与对照组相当。Jassem 等 [47] 的肝移植临床试验研究表明， NMP 能有效保护肝脏功能，减少缺血再灌注损伤。最近发表 的一项国际多中心随机对照试验 [48] 显示，与常规静态冷保存 相比，NMP 组的移植物损伤水平降低了 50%，器官弃用率降…”