Vogels B A, Maas M A, Bosma A, Chamuleau R A
University of Amsterdam, J. van Gool Laboratory for Experimental Internal Medicine, The Netherlands.
Cell Transplant. 1996 May-Jun;5(3):369-78. doi: 10.1177/096368979600500303.
The effect of intrasplenic hepatocyte transplantation (HTX) was studied in an experimental model of acute liver failure in rats with chronic liver atrophy. Rats underwent a portacaval shunt operation on Day -14 to induce liver atrophy, and underwent total hepatectomy on Day 0 as a start of acute liver failure. Intrasplenic hepatocyte or sham transplantation was performed on Day -7,-3, or -1 (n = 4 to 6 per group). During the period following hepatectomy, mean arterial blood pressure was maintained above 80 mm Hg and hypoglycaemia was prevented. Severity of hepatic encephalopathy was assessed by clinical grading and EEG spectral analysis, together with determination of blood ammonia and plasma amino acid concentrations, and "survival" time. Histological examination of the spleen and lungs was performed after sacrifice. Intrasplenic hepatocyte transplantation resulted in a significant improvement in clinical grading in all transplanted groups (p < 0.05), whereas a significant improvement in EEG left index was seen only in the group with transplantation on Day -1 (p < 0.05). In contrast to hepatocyte transplantation 1 day before total hepatectomy, rats with hepatocyte transplantation 3 and 7 days before total hepatectomy showed a significant 3- and 2-fold increase in "survival" time compared to sham transplanted controls: HTX at Day -1: 7.5 +/- 0.3 h vs. 5.9 +/- 0.6 h (p > 0.05), HTX at Day -3: 19.7 +/- 3.7 h vs. 6.5 +/- 0.3 h (p < 0.05), and HTX at Day -7: 13.8 +/- 3.2 h vs. 6.3 +/- 0.3 h (p < 0.05). Furthermore, rats with hepatocyte transplantation on Day -3 and -7 showed significantly lower blood ammonia concentrations after total hepatectomy (p < 0.0001). Histological examination of the spleens after sacrifice showed clusters of hepatocytes in the red pulp. Hepatocytes present in the spleen for 3 and 7 days showed bile accumulation and spots of beginning necrosis. The present data show that in a hard model of complete liver failure in portacaval shunted rats, intrasplenic hepatocyte transplantation is able to prolong "survival" time significantly 2- to 3-fold. The relevance of this observation for human application is discussed.
在患有慢性肝萎缩的大鼠急性肝衰竭实验模型中，研究了脾内肝细胞移植（HTX）的效果。大鼠在第-14天接受门腔分流手术以诱导肝萎缩，并在第0天接受全肝切除术作为急性肝衰竭的起始。在第-7、-3或-1天进行脾内肝细胞移植或假手术移植（每组n = 4至6只）。在肝切除术后的时间段内，平均动脉血压维持在80 mmHg以上，并预防低血糖。通过临床分级和脑电图频谱分析，以及测定血氨和血浆氨基酸浓度和“存活”时间来评估肝性脑病的严重程度。在处死动物后对脾脏和肺进行组织学检查。脾内肝细胞移植使所有移植组的临床分级有显著改善（p < 0.05），而仅在第-1天进行移植的组中脑电图左指数有显著改善（p < 0.05）。与全肝切除术前1天进行肝细胞移植相比，全肝切除术前3天和7天进行肝细胞移植的大鼠的“存活”时间分别比假手术移植对照组显著增加3倍和2倍：第-1天进行HTX：7.5±0.3小时对5.9±0.6小时（p > 0.05），第-3天进行HTX：19.7±3.7小时对6.5±0.3小时（p < 0.05），第-7天进行HTX：13.8±3.2小时对6.3±0.3小时（p < 0.05）。此外，第-3天和-7天进行肝细胞移植的大鼠在全肝切除术后血氨浓度显著降低（p < 0.0001）。处死动物后对脾脏的组织学检查显示红髓中有肝细胞簇。在脾脏中存在3天和7天的肝细胞显示胆汁积聚和开始坏死的斑点。目前的数据表明，在门腔分流大鼠的完全肝衰竭的严格模型中，脾内肝细胞移植能够显著延长“存活”时间2至3倍。讨论了这一观察结果在人类应用中的相关性。
