Mariani P, Coudray-Lucas C, Baudrimont M, Ribeiro J, Legendre C, Delelo R, Cynober L, Balladur P, Nordlinger B
Institut National de la Santé et de la Recherche Médicale U.402, Hôpital Saint-Antoine, Paris, France.
Surgery. 1996 Jul;120(1):93-9. doi: 10.1016/s0039-6060(96)80246-7.
Physiopathology of hepatic encephalopathy remains unclear. Recent studies have suggested that ammonia would not act by itself but through an increase in glutamine in the brain. We have previously demonstrated that transplantation of syngeneic hepatocytes into the spleen was able to correct both behavioral deficits and plasma amino acid changes observed in portacaval shunted rats. The aim of the present work was to show a correlation between the correction of chronic hepatic encephalopathy by means of intrasplenic hepatocyte transplantation and two parameters, brain glutamine concentration and ultrastructural aspects of astrocytes.
Inbred male Wistar Furth rats were divided into three groups: sham-operated rats (n = 10), rats subjected to portacaval shunt (n = 10), and rats subjected to portacaval shunt and intrasplenic hepatocellular transplantation of 10(7) hepatocytes isolated from livers of syngeneic rats (n = 10). Chronic hepatic encephalopathy was quantified 30 and 60 days after operation by means of nose-poke exploration and spontaneous activity. Pathologic examination and measurement of glutamine concentrations in the corpus striatus and in the cerebral cortex were performed 60 days after operation.
Portacaval shunt rats showed reduced spontaneous activity and nose-poke exploration scores. After portacaval shunt a significant glutamine increase occurred in the corpus striatus and in the cerebral cortex when compared with sham rats (p < 0.05). Ultrastructural examination showed modification of astrocytes named Alzheimer type II after portacaval shunt. Correction of behavioral abnormalities by means of intrasplenic hepatocyte transplantation was associated with partial correction of striatal glutamine increase and with decrease in astrocyte alterations. Cortex glutamine concentration in portacaval shunt-intrasplenic hepatocyte transplantation group and in portacaval shunt rats did not differ significantly.
These data show that intrasplenic hepatocyte transplantation not only prevents neurologic disorders of hepatic encephalopathy but can also decrease glutamine and ultrastructural alterations in the corpus striatus in an experimental model of chronic liver failure. These data are in favor of the involvement of glutamine in chronic hepatic encephalopathy. These results suggest that intrasplenic hepatocyte transplantation might be of therapeutic interest in chronic liver failure.
肝性脑病的病理生理学仍不清楚。最近的研究表明，氨本身并无作用，而是通过增加大脑中的谷氨酰胺来发挥作用。我们之前已经证明，将同基因肝细胞移植到脾脏中能够纠正门腔分流大鼠所观察到的行为缺陷和血浆氨基酸变化。本研究的目的是表明通过脾内肝细胞移植纠正慢性肝性脑病与两个参数之间的相关性，即脑谷氨酰胺浓度和星形胶质细胞的超微结构特征。
将近交系雄性Wistar Furth大鼠分为三组：假手术组大鼠（n = 10）、接受门腔分流的大鼠（n = 10）以及接受门腔分流并移植从同基因大鼠肝脏分离的10(7)个肝细胞的脾内肝细胞移植组大鼠（n = 10）。术后30天和60天通过鼻触探索和自发活动对慢性肝性脑病进行量化。术后60天进行病理检查并测量纹状体和大脑皮质中的谷氨酰胺浓度。
门腔分流大鼠的自发活动和鼻触探索得分降低。与假手术大鼠相比，门腔分流后纹状体和大脑皮质中的谷氨酰胺显著增加（p < 0.05）。超微结构检查显示门腔分流后出现了II型阿尔茨海默样星形胶质细胞改变。通过脾内肝细胞移植纠正行为异常与纹状体谷氨酰胺增加的部分纠正以及星形胶质细胞改变的减少相关。门腔分流-脾内肝细胞移植组和门腔分流大鼠的皮质谷氨酰胺浓度无显著差异。
这些数据表明，在慢性肝衰竭的实验模型中，脾内肝细胞移植不仅可以预防肝性脑病的神经功能障碍，还可以降低纹状体中的谷氨酰胺和超微结构改变。这些数据支持谷氨酰胺参与慢性肝性脑病。这些结果表明，脾内肝细胞移植可能对慢性肝衰竭具有治疗意义。
