AUXILIARY PARTIAL ORTHOTOPIC LIVER TRANSPLANTATION FOR FULMINANT HEPATIC FAILURE-PREDICTION AND PROMOTION OF DISEASED LIVER REGENERATION

实验1本研究的目的是通过应用鹅膏毒素和内毒素建立一种临床相关的暴发性肝衰竭(FHF)猪模型。9只猪门静脉注射α-Amanitin+0.1 mg/kg。96小时内全部死亡，24小时天冬氨酸氨基转移酶显著升高(9757±2167IU/L)。此外，他们还表现出严重的代谢紊乱，如血清乳酸蓄积、低血糖、凝血障碍、血浆氨基酸失衡和高氨血症。死亡前即刻颅内压显著升高至17.8±2.5 mm Hg。在这些猪的原位肝移植后，FHF的逆转证实了这种毒性是肝脏特异性的，移植肝没有受到影响。本实验建立了猪辅助性部分原位肝移植(APOLT)模型。取自健康供者的左叶部分肝，在注射毒素和左叶切除后原位移植于受体。所有的猪在APOLT后存活超过2周。APOLT后一周的肝活检标本显示病变的天然肝脏再生。即使在一周后结扎左门静脉和左肝动脉，猪仍存活下来，肝功能令人满意。因此，我们建立了一种猪APOLT模型，利用我们新开发的方法，使用Amanitin和LPS诱导FHF，在该模型中，在没有门静脉分流的情况下，移植物的血液供应充足。病变的天然肝脏的再生似乎在大约一周内完成，移植肝流入阻断后的存活证实了其功能的完全恢复。

<Experiment 1> The purpose of this study was to develop a clinically relevant porcine model of fulminant hepatic failure (FHF) by means of administration of amatoxin and endotoxin. Pigs were intraportally administered 0.1 mg/kg of alpha-amanitin plus (n=9). All the pigs died within 96 hours with a significant increase in AST at 24 hr (9757±2167 IU/L). In addition, they demonstrated severe metabolic disorders such as serum lactate accumulation, hypoglycemia, coagulopathy, plasma amino acid imbalance, and hyperammonemia. Intracranial pressure significantly increased to 17.8±2.5 mm Hg immediately before death. Reversal of FHF in these pigs following orthotopic liver transplantation confirmed that the toxicity is liver-specific and that the graft liver is unaffected. This porcine model of FHF induced by a combination of amanitin and LPS will be of much use in the development of new therapies for human FHF.<Experiment 2> A porcine auxiliary partial orthotopic liver transplantation (APOLT) model for FHF was developed in the next study. A left lobe partial liver graft procured from a healthy donor was transplanted in the recipient in the orthotopic position after the toxin administration and left lobectomy. All the pigs survived more than 2 weeks after APOLT.Liver biopsy specimens one week after APOLT revealed regeneration of the diseased native liver. Even after the ligation of the left portal vein and left hepatic artery at one week, pigs subsequently survived with satisfactory liver function. Thus, we have established a porcine APOLT model against FHF induced by our newly developed method using amanitin and LPS.In this model, blood supply to the grafts was sufficient without portal diversion. Regeneration of the diseased native liver appeared to be accomplished in about one week, and full restoration of its function was confirmed by the survival after inflow occlusion of the graft liver.