Division of Transplant Surgery, Department of Surgery, Medical College of Wisconsin, Milwaukee WI.
Transplant Center, Froedtert & the Medical College of Wisconsin, and Children's Wisconsin, Milwaukee, WI.
Ann Surg. 2023 Feb 1;277(2):e366-e375. doi: 10.1097/SLA.0000000000005156. Epub 2023 Jan 10.
We sought to investigate the biological effects of pre-reperfusion treatments of the liver after warm and cold ischemic injuries in a porcine donation after circulatory death model.
Donation after circulatory death represents a severe form of liver ischemia and reperfusion injury that has a profound impact on graft function after liver transplantation.
Twenty donor pig livers underwent 60 minutes of in situ warm ischemia after circulatory arrest and 120 minutes of cold static preservation prior to simulated transplantation using an ex vivo perfusion machine. Four reperfusion treatments were compared: Control-Normothermic (N), Control- Subnormothermic (S), regulated hepatic reperfusion (RHR)-N, and RHR-S (n = 5 each). The biochemical, metabolic, and transcriptomic profiles, as well as mitochondrial function were analyzed.
Compared to the other groups, RHR-S treated group showed significantly lower post-reperfusion aspartate aminotransferase levels in the reperfusion effluent and histologic findings of hepatocyte viability and lesser degree of congestion and necrosis. RHR-S resulted in a significantly higher mitochondrial respiratory control index and calcium retention capacity. Transcriptomic profile analysis showed that treatment with RHR-S activated cell survival and viability, cellular homeostasis as well as other biological functions involved in tissue repair such as cytoskeleton or cytoplasm organization, cell migration, transcription, and microtubule dynamics. Furthermore, RHR-S inhibited organismal death, morbidity and mortality, necrosis, and apoptosis.
Subnormothermic RHR mitigates IRI and preserves hepatic mitochondrial function after warm and cold hepatic ischemia. This organ resuscitative therapy may also trigger the activation of protective genes against IRI. Sub- normothermic RHR has potential applicability to clinical liver transplantation.
在猪模型中，我们研究了热缺血和冷缺血损伤后再灌注前肝脏预处理的生物学效应。
在循环死亡后的捐赠代表了一种严重的肝缺血再灌注损伤形式，对肝移植后移植物功能有深远影响。
20 个供体猪肝脏在循环停止后经历了 60 分钟的原位热缺血，然后在使用离体灌注机进行模拟移植前进行了 120 分钟的冷静态保存。比较了 4 种再灌注处理：对照-常温（N）、对照-亚常温（S）、调节性肝再灌注（RHR）-N 和 RHR-S（每组各 5 例）。分析了生化、代谢和转录组谱以及线粒体功能。
与其他组相比，RHR-S 处理组在再灌注流出物中显示出较低的天冬氨酸转氨酶水平，组织学检查发现肝细胞活力和充血坏死程度较低。RHR-S 导致线粒体呼吸控制指数和钙保留能力显著提高。转录组谱分析显示，RHR-S 处理激活了细胞存活和活力、细胞内稳态以及其他涉及组织修复的生物学功能，如细胞骨架或细胞质组织、细胞迁移、转录和微管动力学。此外，RHR-S 抑制了机体死亡、发病率和死亡率、坏死和凋亡。
亚常温 RHR 减轻了热缺血和冷缺血后的肝缺血再灌注损伤，并保存了肝线粒体功能。这种器官复苏治疗可能还会触发针对 IRI 的保护性基因的激活。亚常温 RHR 具有潜在的临床肝移植应用前景。
