Taggart McLean, Holkup Saige, Tchir Alexandra, Mojoudi Mohammadreza, Lyon Arnaud, Hassan Madeeha, Taveras Christopher, Ozgur Ozge Sila, Markmann James F, Yeh Heidi, Uygun Korkut, Longchamp Alban
Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Shriners Children's Boston, Boston, MA, USA.
Sci Rep. 2025 Jan 10;15(1):1559. doi: 10.1038/s41598-025-85302-w.
Static cold storage of donor livers at 4 °C incompletely arrests metabolism, ultimately leading to decreases in ATP levels, oxidative stress, cell death, and organ failure. Hydrogen Sulfide (HS) is an endogenously produced gas, previously demonstrated to reduce oxidative stress, reduce ATP depletion, and protect from ischemia and reperfusion injury. HS is difficult to administer due to its rapid release curve, resulting in cellular death at high concentrations. AP39, a mitochondrially targeted, slow-release HS donor, has been shown to reduce ischemia-reperfusion injury in hearts and kidneys. Thus, we investigated whether the addition of AP39 during 3-day static cold storage can improve liver graft viability. At the end of storage, livers underwent six hours of acellular normothermic machine perfusion, a model of transplantation. During simulated transplantation, livers stored with AP39 showed reduced resistance, reduced cellular damage (ALT and AST), and reduced apoptosis. Additionally, bile production and glucose, as well as energy charge were improved by the addition of AP39. These results indicate that AP39 supplementation improves liver viability during static cold storage.
在4°C下对供体肝脏进行静态冷藏并不能完全抑制新陈代谢，最终会导致三磷酸腺苷（ATP）水平降低、氧化应激、细胞死亡和器官衰竭。硫化氢（HS）是一种内源性产生的气体，先前已证明它能减轻氧化应激、减少ATP消耗，并预防缺血再灌注损伤。由于HS的快速释放曲线，难以给药，高浓度时会导致细胞死亡。AP39是一种靶向线粒体的缓释HS供体，已证明其能减轻心脏和肾脏的缺血再灌注损伤。因此，我们研究了在3天静态冷藏期间添加AP39是否能提高肝脏移植物的活力。在储存结束时，肝脏进行了6小时的无细胞常温机器灌注，这是一种移植模型。在模拟移植过程中，添加AP39储存的肝脏显示阻力降低、细胞损伤（谷丙转氨酶和谷草转氨酶）减少以及细胞凋亡减少。此外，添加AP39可改善胆汁生成、葡萄糖水平以及能量状态。这些结果表明，补充AP39可提高静态冷藏期间肝脏的活力。
