Eguchi S, Lilja H, Hewitt W R, Middleton Y, Demetriou A A, Rozga J
Department of Surgery, UCLA School of Medicine, Los Angeles, California 90048, USA.
J Surg Res. 1997 Oct;72(2):112-22. doi: 10.1006/jsre.1997.5175.
We earlier described a model of fulminant hepatic failure (FHF) in the rat where partial hepatectomy is combined with induction of right liver lobes necrosis. After this procedure, lack of regenerative response in the residual viable liver tissue (omental lobes) was associated with elevated plasma hepatocyte growth factor (HGF) and transforming growth factor beta (TGF-beta1) levels and delayed expression of HGF and c-met mRNA in the remnant liver. Here, we investigated whether syngeneic isolated hepatocytes transplanted in the spleen will prolong survival and facilitate liver regeneration in FHF rats. Inbred male Lewis rats were used. Group I rats (n = 46) received intrasplenic injection of 2 x 10(7) hepatocytes and 2 days later FHF was induced. Group II FHF rats (n = 46) received intrasplenic injection of saline. Rats undergoing partial hepatectomy of 68% (PH; n = 30) and a sham operation (SO; n = 30) served as controls. In 20 FHF rats (10 rats/group), survival time was determined. The remaining 72 FHF rats (36 rats/group) were used for physiologic studies (liver function and regeneration and plasma growth factor levels). In Group I rats survival was longer than that of Group II controls (73 +/- 22 hr vs. 33 +/- 9 hr; P < 0. 01). During the first 36 hr, Group I rats had lower blood ammonia, lactate, total bilirubin, PT, and PTT values, lower activity of liver enzymes, and higher monoethylglycinexylidide (MEGX) production than Group II rats. In Group I rats, livers increased in weight at a rate similar to that seen in PH controls and showed distinct mitotic and DNA synthetic activity (incorporation of bromodeoxyuridine and proliferation cell nuclear antigen expression). Plasma HGF and TGF-beta1 levels in these rats decreased and followed the pattern seen in PH rats; additionally, c-met expression in the remnant liver was accelerated. Hepatocyte transplantation prolonged survival in FHF rats and facilitated liver regeneration. Even though the remnant liver increased in weight four times reaching 30% of the original liver mass, the transplant-bearing rats expired due to inability of the regenerating liver to support the rat.
我们之前描述了一种大鼠暴发性肝衰竭（FHF）模型，该模型是将部分肝切除术与诱导右肝叶坏死相结合。在此手术后，残余存活肝组织（网膜叶）缺乏再生反应与血浆肝细胞生长因子（HGF）和转化生长因子β（TGF-β1）水平升高以及残余肝脏中HGF和c-met mRNA表达延迟有关。在此，我们研究了脾脏移植同基因分离的肝细胞是否会延长FHF大鼠的存活时间并促进肝脏再生。使用近交系雄性Lewis大鼠。I组大鼠（n = 46）接受脾脏内注射2×10⁷个肝细胞，2天后诱导FHF。II组FHF大鼠（n = 46）接受脾脏内注射生理盐水。接受68%部分肝切除术（PH；n = 30）和假手术（SO；n = 30）的大鼠作为对照。在20只FHF大鼠（每组10只大鼠）中测定存活时间。其余72只FHF大鼠（每组36只大鼠）用于生理学研究（肝功能、再生和血浆生长因子水平）。I组大鼠的存活时间长于II组对照（73±22小时对33±9小时；P < 0.01）。在最初的36小时内，I组大鼠的血氨、乳酸、总胆红素、PT和PTT值较低，肝酶活性较低，单乙基甘氨酰二甲苯胺（MEGX）生成较高。在I组大鼠中，肝脏重量增加的速率与PH对照组相似，并显示出明显的有丝分裂和DNA合成活性（溴脱氧尿苷掺入和增殖细胞核抗原表达）。这些大鼠血浆中的HGF和TGF-β1水平下降，并遵循PH大鼠中观察到的模式；此外，残余肝脏中c-met的表达加速。肝细胞移植延长了FHF大鼠的存活时间并促进了肝脏再生。尽管残余肝脏重量增加了四倍，达到原始肝脏质量的30%，但携带移植肝细胞的大鼠因再生肝脏无法维持大鼠生命而死亡。
