NIM811 可预防肝大部切除术后的线粒体功能障碍，减轻肝损伤，促进肝脏再生。
NIM811 prevents mitochondrial dysfunction, attenuates liver injury, and stimulates liver regeneration after massive hepatectomy.
机构信息
Department of Pharmaceutical and Biomedical Sciences, Medical University of South Carolina, Charleston, SC, USA.
出版信息
Transplantation. 2011 Feb 27;91(4):406-12. doi: 10.1097/TP.0b013e318204bdb2.
BACKGROUND
Massive hepatectomy (MHX) leads to failure of remnant livers. Excessive metabolic burden in remnant livers may cause mitochondrial dysfunction. This study investigated whether blockade of the mitochondrial permeability transition (MPT) with N-methyl-4-isoleucine cyclosporine (NIM811) improves the outcome of MHX.
METHODS
Mice were gavaged with NIM811 (10 mg/kg before surgery and 5 mg/kg daily afterward) and underwent sham-operation or approximately 90% partial hepatectomy.
RESULTS
Serum alanine aminotransferase, necrosis, and apoptosis increased, respectively, to approximately 1200 U/L, 6.1%, and 7% after MHX. NIM811 decreased peak alanine aminotransferase release, necrosis, and apoptosis by 70%, 100%, and 42%, respectively. 5-Bromo-2'-deoxyuridine incorporation, proliferating cell nuclear antigen expression, and the remnant liver weights were all increased significantly by NIM811 treatment, indicating improved liver regeneration. NIM811 also blunted hyperbilirubinemia by 54%, increased serum albumin by 51%, and improved survival from 6% to 40% after MHX. Hepatic mitochondrial depolarization, cell death, and MPT were detected by intravital confocal/multiphoton microscopy of rhodamine 123, propidium iodide, and calcein. Mitochondrial depolarization occurred in many viable hepatocytes (13 cells/high-power field), and nonviable hepatocytes increased slightly to approximately 1 cell/high-power field at 3 hr after MHX. Entry of calcein into mitochondria after MHX indicated MPT onset. Importantly, NIM811 decreased mitochondria depolarization by more than 60%, blocked MPT onset, and prevented cell death. Decreases of hepatic ATP, mitochondrial cytochrome c release, and caspase-3 activation after MHX were also partially blocked by NIM811.
CONCLUSIONS
NIM811 minimized liver injury and improved liver regeneration after MHX, at least in part, by preventing MPT onset and subsequent compromised energy supply and proapoptotic cytochrome c release.
背景
大范围肝切除术（MHX）导致残余肝脏功能衰竭。残余肝脏代谢负担过重可能导致线粒体功能障碍。本研究旨在探讨使用 N-甲基-4-异亮氨酸环孢菌素（NIM811）阻断线粒体通透性转换（MPT）是否可以改善 MHX 术后的结果。
方法
小鼠术前给予 NIM811（10mg/kg，术后每日 5mg/kg）灌胃，并进行假手术或约 90%部分肝切除术。
结果
MHX 后血清丙氨酸氨基转移酶、坏死和凋亡分别增加到约 1200U/L、6.1%和 7%。NIM811 使丙氨酸氨基转移酶峰值释放、坏死和凋亡分别减少 70%、100%和 42%。NIM811 治疗显著增加了 5-溴-2'-脱氧尿苷掺入、增殖细胞核抗原表达和残余肝重，表明肝再生改善。NIM811 还使胆红素血症降低 54%，血清白蛋白增加 51%，MHX 后生存率从 6%提高到 40%。通过 rhodamine 123、碘化丙啶和 calcein 的活体共聚焦/多光子显微镜检测肝线粒体去极化、细胞死亡和 MPT。MHX 后许多存活的肝细胞（高倍视野 13 个细胞）发生线粒体去极化，非存活的肝细胞略有增加，高倍视野约 1 个细胞。MHX 后 calcein 进入线粒体表明 MPT 开始。重要的是，NIM811 使线粒体去极化减少超过 60%，阻断 MPT 起始，并防止细胞死亡。NIM811 还部分阻断了 MHX 后肝 ATP、线粒体细胞色素 c 释放和 caspase-3 激活的减少。
结论
NIM811 通过防止 MPT 起始和随后的能量供应受损以及促凋亡细胞色素 c 释放，最大限度地减少 MHX 后肝损伤并改善肝再生，至少部分如此。
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