Clinical and experimental study for regulation of apoptosis and necrosis in acute liver failure

急性肝衰竭细胞凋亡和坏死调控的临床与实验研究

• 批准号: 10670497
• 负责人: SUZUKI Kazuyuki
• 金额: $ 1.66万
• 依托单位: Iwate Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670497/
• 关键词: acute liver failure; Fulminant hepatitis; liver necrosis; anootosis; Fas ligand; TNF receptor; glucocoryicoid; immunosuppressive drug; ネクローシス; サイトカイン

(1) Clinical study: we measured the serum levels of soluble Fas, Fas ligand(FasL), tumor necrosis factor alfa (TNF α) and TNF receptor-1(TNFR1) in patients with acute hepatitis (AH) and fulminant hepatitis(FH). We also evaluated the relationship between these parameters and the prognosis of disease. The serum sFas and sFasL levels were significantly increased in patients with AH and FH compared to that in normal subjects. However, there were no differences between AH and FH. The serum TNF a and TNFR1 were also significantly increased in patients with AH and FH. In paticular, the serum TNFR1 levels were significantly increased in patients with FH compared to that of AH patients, and it reflected the severity of liver damage and the prognosis of hepatitis. Our data suggest that the Fas-FasL system and TNFα and TNFR1 are closely associated with the early process of massive hepatic necrosis.(2) Experimental study: we evaluated whether the administration of glucocorticoid and cyclosporin A could protect acute liver injury induced by galactosamin and lipopolysaccharide in rats. The glucocorticoid inhibited both TNFα production and apoptosis, resulting in the protection of the development of massive liver necrosis. On the other hand, cyclospolin A was also protective against acute liver injury, if it is administered at an apopriate time during the course of liver injury. Although cyclosporin A did not inhibit both TNFα production and apoptosis, it inhibited the neutrophil infiltration into the liver tissue. Further studies are needed to clarify the mechanisms of the effect of these druges on acute liver injury model.

(1)临床研究：检测了急性肝炎（AH）和重型肝炎（FH）患者血清可溶性Fas、Fas配体（FasL）、肿瘤坏死因子α（TNF α）和肿瘤坏死因子受体1（TNFR 1）的水平。我们还评估了这些参数与疾病预后之间的关系。AH和FH患者血清sFas和sFasL水平明显高于正常人。然而，AH和FH之间没有差异。AH和FH患者血清TNF a和TNFR 1也明显升高。FH患者血清TNFR 1水平较AH患者明显升高，可反映肝损害的严重程度及肝炎的预后。提示Fas FasL系统和TNFα、TNFR 1与肝大面积坏死的早期过程密切相关。(2)实验研究：本实验观察了糖皮质激素和环孢素A对半乳糖胺和脂多糖诱导的大鼠急性肝损伤的保护作用。糖皮质激素抑制TNFα的产生和细胞凋亡，从而保护大面积肝坏死的发展。另一方面，如果在肝损伤过程中的适当时间给予环胞菌素A，也可以预防急性肝损伤。环孢菌素A虽然不能抑制TNFα的产生和细胞凋亡，但能抑制中性粒细胞向肝组织的浸润。这些药物对急性肝损伤模型的作用机制有待进一步研究。

项目成果

佐藤彰宏、他: "ラット急性肝不全モデルに対する糖質コルチコイド治療の有効性に関する検討"肝臓. 40. 217-225 (1999)

Akihiro Sato 等人：“糖皮质激素治疗急性肝衰竭大鼠模型的有效性研究”，肝脏，40. 217-225 (1999)。

佐藤彰宏、他3名: "ラット急性肝不全モデルに対する糖質コルチコイド治療の有効性に関する検討"肝臓. 40・4. 17-26 (1999)

Akihiro Sato，其他3人：“糖皮质激素治疗大鼠急性肝衰竭模型的有效性研究”肝脏，40，4.17-26（1999）。

T. Kawakami, et al: "Bedeficial effect of cyclosporin A on acute hepatic injury induced by galactosamine and lipopolysaccharide in rats."Hepatology Research. (in press). (2000)

T. Kawakami 等人：“环孢菌素 A 对半乳糖胺和脂多糖诱导的大鼠急性肝损伤的有益作用。”肝病学研究。

K Suzuki, et al: "Serum levels of soluble Fas ligand in patients with acute and fulminant hepatitis: relationship with soluble Fas. Tumor necrosis factor alfa and TNF receptor-1"Hepatology Reseach. 17. 17-30 (2000)

K Suzuki 等人：“急性和暴发性肝炎患者中可溶性 Fas 配体的血清水平：与可溶性 Fas 的关系。肿瘤坏死因子 α 和 TNF 受体-1”肝病学研究。

佐藤彰宏 他3名: "ラット急性肝不全モデルに対する糖質コルチコイド治療の有効性に関する検討" 肝臓. 40・4(予定). (1999)

Akihiro Sato 和其他 3 人：“糖皮质激素治疗急性肝衰竭大鼠模型的有效性研究”40/4（计划）（1999 年）。