Ohnishi H, Muto Y, Maeda T, Hayashi T, Nagaki M, Yamada T, Shimazaki M, Yamada Y, Sugihara J, Moriwaki H
First Department of Internal Medicine, Gifu University School of Medicine, Japan.
Gastroenterol Jpn. 1993 Mar;28 Suppl 4:40-4; discussion 53-6. doi: 10.1007/BF02782888.
The authors established a new experimental model of fulminant hepatic failure (FHF) with prolonged hepatocellular necrosis and impaired liver regeneration, and evaluated the immunological mechanisms related to the impaired liver regeneration in this model. A novel lipid A analogue, FS-112, was injected intravenously into male Balb/c mice, followed by a 70% partial hepatectomy 2 days later. Serum levels of T.Bil. and ALT rose 7 days after the partial hepatectomy, as compared with controls. In mice pretreated with FS-112, labeling indices of both BrdU and PCNA 36 hrs after the partial hepatectomy were significantly lower than those in the controls. Splenic lymphocytes harvested from the FHF mice 1-5 days after the partial hepatectomy showed a cytotoxic activity against regenerating hepatocytes with a peak effect on day 5. Cytotoxic activity against YAC-1 cells was also found up to 5 days after the partial hepatectomy, and resembled that directed against the regenerating hepatocytes. On the 5th day of FS-112 administration, there was a marked rise in the production of IFN-gamma from splenocytes. When FK-506, an immunosuppressive agent, was given intracutaneously daily for 7 days, serum levels of T.Bil. and ALT significantly decreased, as compared with controls. Furthermore, the PCNA-labeling index 36 hrs after the partial hepatectomy was enhanced by the administration with FK-506 in the FHF mice. These results strongly suggest that the NK cells activated by IFN-gamma may be involved in killing the regenerating liver cells, and thus play a role in the pathogenesis of the impaired liver regeneration in FHF.2+ recovery from the impaired liver regeneration in FHF.
作者建立了一种新的暴发性肝衰竭（FHF）实验模型，该模型具有延长的肝细胞坏死和受损的肝再生，并评估了此模型中与受损肝再生相关的免疫机制。将一种新型脂质A类似物FS-112静脉注射到雄性Balb/c小鼠体内，2天后进行70%的部分肝切除术。与对照组相比，部分肝切除术后7天血清总胆红素（T.Bil.）和谷丙转氨酶（ALT）水平升高。在接受FS-112预处理的小鼠中，部分肝切除术后36小时的BrdU和PCNA标记指数均显著低于对照组。部分肝切除术后1 - 5天从FHF小鼠收集的脾淋巴细胞对再生肝细胞表现出细胞毒性活性，在第5天达到峰值效应。部分肝切除术后长达5天也发现对YAC-1细胞的细胞毒性活性，且与对再生肝细胞的活性相似。在给予FS-112的第5天，脾细胞产生的γ干扰素明显增加。当每天皮内给予免疫抑制剂FK-506共7天时，与对照组相比，血清T.Bil.和ALT水平显著降低。此外，在FHF小鼠中，给予FK-506可提高部分肝切除术后36小时的PCNA标记指数。这些结果强烈表明，由γ干扰素激活的自然杀伤细胞（NK细胞）可能参与杀死再生肝细胞，从而在FHF受损肝再生的发病机制中起作用。FHF中受损肝再生的恢复。
