Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, Ajmera Transplant Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
Departments of Pharmacology & Toxicology and Psychiatry, The Canada Mitochondrial Network, University of Toronto, Toronto, ON M5S 1A8, Canada.
EBioMedicine. 2022 Sep;83:104210. doi: 10.1016/j.ebiom.2022.104210. Epub 2022 Aug 8.
Cold static preservation (CSP) at higher temperatures (10°C) has been recently shown as an optimal strategy up to 24-36h of preservation. Here, we hypothesized that alternating 10°C static storage with cycles of normothermic ex vivo lung perfusion (EVLP) would provide conditions for cellular "recharge", allowing for multi-day lung preservation.
Donor lungs from male Yorkshire pigs were preserved using 10°C CSP with two cycles of 4h EVLP. After a total of 3 days of preservation, a left lung transplant was performed followed by 4h of graft evaluation. As controls, 2 lungs were preserved solely with continuous 10°C preservation for 3 days and transplanted.
For animals receiving lungs preserved using a cyclic EVLP protocol, lung function and histological structures were stable and the recipient systemic partial pressure of oxygen/fraction of inspired oxygen (P/F Ratio) after excluding the contralateral lung was 422 ± 61 mmHg. In contrast, lungs preserved solely in continuous cold static storage at 10°C for 72h developed massive lung failure, resulting in recipient death. Metabolomic analysis revealed that EVLP plays a critical role in the re-vitalization of key central carbon energy metabolites (Glucose, Succinate, N-Acetyl Aspartate) and reducing the expression of the inflammasome activation marker CASP1.
In conclusion, we demonstrate for the first time the feasibility of 3-day lung preservation leading to excellent early post-transplant outcomes. The thoughtful combination of cold storage (10°C) and intermittent EVLP can open new opportunities in organ transplantation.
This work was supported by the UHN Foundation (Grant#1013612).
最近的研究表明，在较高温度（10°C）下进行冷静态保存（CSP）可以作为 24-36 小时保存的最佳策略。在这里，我们假设用常温离体肺灌注（EVLP）循环交替 10°C 静态储存，为细胞“充电”提供条件，从而实现多日肺保存。
使用 10°C CSP 与两个 4 小时 EVLP 周期对雄性约克夏猪供体肺进行保存。在总共 3 天的保存后，进行左肺移植，并进行 4 小时的移植物评估。作为对照，2 个肺只用连续 10°C 保存 3 天进行移植。
对于接受循环 EVLP 方案保存的肺的动物，肺功能和组织学结构稳定，排除对侧肺后受体系统的氧分压/吸入氧分数（P/F 比值）为 422±61mmHg。相比之下，仅在 10°C 连续冷静态储存 72 小时的肺会发生严重的肺衰竭，导致受体死亡。代谢组学分析表明，EVLP 在关键中心碳能量代谢物（葡萄糖、琥珀酸、N-乙酰天冬氨酸）的再激活中发挥关键作用，并降低炎症小体激活标记物 CASP1 的表达。
我们首次证明了 3 天肺保存导致良好的早期移植后结果的可行性。冷储存（10°C）和间歇性 EVLP 的巧妙结合为器官移植开辟了新的机会。
这项工作得到了 UHN 基金会（Grant#1013612）的支持。
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