Matot Idit, Nachmansson Nathalie, Duev Omri, Schulz Susanne, Schroeder-Stein Katrin, Frede Stilla, Abramovitch Rinat
Division of Anesthesiology, Intensive Care, and Pain, Tel-Aviv Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
The Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
FASEB J. 2017 Dec;31(12):5283-5295. doi: 10.1096/fj.201700153R. Epub 2017 Aug 8.
Extensive liver resections are common, and bleeding is frequent in these operations. Impaired regeneration after partial hepatectomy (PHx) may contribute to liver failure. We thus assessed the impact of acute bleeding on the liver regeneration progress after PHx and explored possible contributing molecular mechanisms. In rats, the regeneration progress was delayed and attenuated with PHx and bleeding and was not restored with colloid resuscitation. Livers restored their initial volume by postoperative day (POD) 2 after PHx through hepatocyte proliferation POD 4 in the PHx and bleeding group, primarily by hepatocyte hypertrophy. With bleeding, hepatocyte proliferation was hindered in two mechanisms: by inhibiting cells from starting proliferation and by causing hindrance in G/S progression. Liver hypoxia was prominent, with significant prolonged up-regulation of hypoxia-inducible factors (HIF) and HIF-targeted genes only in the PHx and bleeding group. Gene expression profiling revealed alterations in numerous genes that belong to critical pathways, including cell cycle, DNA replication, PI3K-Akt, purine, and pyrimidine metabolism. Because liver surgery is frequently performed in patients with a predamaged liver, an improper regenerative process after PHx and bleeding might lead to decompensation. The results hint at specific pathways to target in order to improve liver regeneration during PHx and bleeding.-Matot, I., Nachmansson, N., Duev, O., Schulz, S., Schroeder-Stein, K., Frede, S., Abramovitch, R. Impaired liver regeneration after hepatectomy and bleeding is associated with a shift from hepatocyte proliferation to hypertrophy.
广泛肝切除术很常见，且此类手术中出血频繁。部分肝切除术后（PHx）肝脏再生受损可能导致肝衰竭。因此，我们评估了急性出血对PHx后肝脏再生进程的影响，并探讨了可能的相关分子机制。在大鼠中，PHx加出血后肝脏再生进程延迟且减弱，胶体复苏无法使其恢复。PHx组术后第2天（POD 2）肝脏通过肝细胞增殖恢复至初始体积，而PHx加出血组在POD 4时主要通过肝细胞肥大恢复。出血时，肝细胞增殖受两种机制阻碍：抑制细胞开始增殖以及导致G/S期进程受阻。肝脏缺氧明显，仅在PHx加出血组中缺氧诱导因子（HIF）及其靶向基因显著上调且持续时间延长。基因表达谱分析显示众多属于关键通路的基因发生改变，包括细胞周期、DNA复制、PI3K-Akt、嘌呤和嘧啶代谢。由于肝手术常施于肝脏已受损的患者，PHx加出血后不适当的再生过程可能导致失代偿。这些结果提示了可作为靶点的特定通路，以便在PHx加出血期间改善肝脏再生。-马托特，I.，纳赫曼松，N.，杜耶夫，O.，舒尔茨，S.，施罗德 - 施泰因，K.，弗雷德，S.，阿布拉莫维奇，R.肝切除术后出血导致肝脏再生受损与从肝细胞增殖向肥大的转变有关。
