Yazdani Hamza O, Yang Ruiqi, Haykal Tony, Tohme Celine, Kaltenmeier Christof, Wang Ronghua, Nakano Ryosuke, Nigmet Yermek, Gambella Alessandro, Loughran Patricia, Hughes Christopher B, Geller David A, Tohme Samer
Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA.
McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA.
Transplantation. 2025 Jan 1;109(1):161-173. doi: 10.1097/TP.0000000000005176. Epub 2024 Aug 22.
Liver transplantation stands as the primary treatment for end-stage liver disease, with demand surging in recent decades because of expanded indications. However, hepatic ischemia/reperfusion injury can lead to liver transplant failure in both deceased donor and living donor transplantation. This study explored whether preconditioning donor livers through exercise training (ExT) could mitigate cold ischemic injury posttransplantation.
Donor C57BL/6 mice underwent ExT via treadmill running or remained sedentary. After 4 wk, the donor liver underwent cold storage and subsequent orthotopic liver transplantation or ex vivo warm reperfusion.
Donor liver from mice subjected to ExT showed significantly decreased hepatic injury on reperfusion. Tissue histology revealed decreased sinusoidal congestion, vacuolization, and hepatocellular necrosis in livers from ExT mice, and immunofluorescence staining further revealed a decreased number of apoptotic cells in ExT grafts. Livers from ExT donors expressed decreased intragraft inflammatory cytokines cascade, decreased neutrophil infiltration and neutrophil extracellular traps, and increased M2 phenotype of recipient macrophages compared with grafts from sedentary mice. After cold storage, liver grafts from ExT donors showed decreased accumulation of reactive oxygen species and decreased levels of cytochrome c and high mobility group box 1 released in the liver effluent. In addition, ExT grafts showed upregulated peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and higher levels of mitochondrial content. Similar effects of decreased hepatic injury were observed in wild-type mice when pretreated with a PGC-1α stimulator ZLN005 instead of ExT.
These findings suggest that augmenting hepatocytic mitochondrial content through donor exercise or PGC-1α stimulation may offer therapeutic avenues to mitigate postreperfusion inflammation and improve transplant outcomes.
肝移植是终末期肝病的主要治疗方法，近几十年来，由于适应症的扩大，需求激增。然而，肝缺血/再灌注损伤可导致死体供肝和活体供肝移植的肝移植失败。本研究探讨通过运动训练（ExT）对供肝进行预处理是否可以减轻移植后的冷缺血损伤。
供体C57BL/6小鼠通过跑步机跑步进行ExT或保持久坐不动。4周后，供肝进行冷藏，随后进行原位肝移植或体外温血再灌注。
接受ExT的小鼠的供肝在再灌注时肝损伤明显减轻。组织学检查显示，ExT小鼠肝脏的窦状隙充血、空泡化和肝细胞坏死减少，免疫荧光染色进一步显示ExT移植物中凋亡细胞数量减少。与久坐小鼠的移植物相比，ExT供体的肝脏移植物内炎症细胞因子级联反应减少，中性粒细胞浸润和中性粒细胞胞外陷阱减少，受体巨噬细胞的M2表型增加。冷藏后，ExT供体的肝移植物显示活性氧积累减少，肝流出液中细胞色素c和高迁移率族蛋白B1水平降低。此外，ExT移植物显示过氧化物酶体增殖物激活受体γ辅激活因子1-α（PGC-1α）上调，线粒体含量更高。当用PGC-1α刺激剂ZLN005而非ExT预处理时，在野生型小鼠中也观察到类似的肝损伤减轻效果。
这些发现表明，通过供体运动或PGC-1α刺激增加肝细胞线粒体含量可能为减轻再灌注后炎症和改善移植结果提供治疗途径。
