Li Zheyong, Liang Yuelong, Ying Hanning, Chen Mingyu, He Xiaoyan, Wang Yifan, Tong Yifan, Cai Xiujun
Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Ann Transl Med. 2021 Apr;9(7):527. doi: 10.21037/atm-20-4639.
The mechanism of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS)-induced rapid liver regeneration remains poorly documented, especially in patients with fibrosis. Therefore, this study aims to investigate the underlying mechanism of ALPPS-induced accelerated regeneration in toxin-induced fibrosis models.
The ALPPS-induced regeneration model was established in livers with thioacetamide (TAA)-induced fibrosis to determine the regenerative pathways involved in rapid regeneration. Confirmatory experiments were performed in transforming growth factor beta 1 (TGFβ1)-treated AML12 cells and mice with carbon tetrachloride (CCl)-induced fibrosis. Finally, mitochondrial dysfunction was validated in fibrotic/non-fibrotic patients.
In TAA-induced fibrotic mice, ALPPS-induced regeneration was significantly inferior to that of the control group (P=0.027 at day 2 and P<0.001 at day 7). Furthermore, mitochondria-associated genes were significantly downregulated in TAA-challenged mice. Accordingly, the reduced production of ATP and elevated levels of malondialdehyde indicated disturbances in intracellular energy metabolism during the ALPPS-induced regenerative process after TAA treatment. Further investigations were performed in TGF-β1-treated AML12 cells and CCl-treated mice, which indicated that mitochondrial dysfunction attenuated the capacity for rapid regeneration after ALPPS.
In summary, this study revealed that mitochondrial dysfunction led to inferior regeneration in livers with toxin-induced fibrosis and identified new therapeutic targets to improve the feasibility and safety of the ALPPS procedure. Further studies in human patients are required in the future.
联合肝脏分隔和门静脉结扎分期肝切除术（ALPPS）诱导肝脏快速再生的机制仍缺乏充分的文献记载，尤其是在纤维化患者中。因此，本研究旨在探讨ALPPS在毒素诱导的纤维化模型中加速肝脏再生的潜在机制。
在硫代乙酰胺（TAA）诱导纤维化的肝脏中建立ALPPS诱导的再生模型，以确定快速再生所涉及的再生途径。在转化生长因子β1（TGFβ1）处理的AML12细胞和四氯化碳（CCl）诱导纤维化的小鼠中进行验证实验。最后，在纤维化/非纤维化患者中验证线粒体功能障碍。
在TAA诱导的纤维化小鼠中，ALPPS诱导的再生明显低于对照组（第2天P = 0.027，第7天P < 0.001）。此外，在TAA攻击的小鼠中，线粒体相关基因显著下调。因此，ATP生成减少和丙二醛水平升高表明TAA处理后ALPPS诱导的再生过程中细胞内能量代谢紊乱。在TGF-β1处理的AML12细胞和CCl处理的小鼠中进行了进一步研究，结果表明线粒体功能障碍减弱了ALPPS后快速再生的能力。
总之，本研究表明线粒体功能障碍导致毒素诱导纤维化肝脏的再生能力下降，并确定了新的治疗靶点，以提高ALPPS手术的可行性和安全性。未来需要在人类患者中进行进一步研究。
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