The Mechanisms of Impaired Liver Regeneration in Fulminant Hepatic Failure : The Significance of Sinusoidal Endothelial Cell Proliferation.

暴发性肝衰竭中肝脏再生受损的机制：正弦内皮细胞增殖的意义。

• 批准号: 09670571
• 负责人: MOCHIDA Satoshi
• 金额: $ 2.3万
• 依托单位: Saitama Medical School
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09670571/
• 关键词: Liver Regeneration; Fulminant Hepatic Failure; Sinusoidal Endothelial Cells; VEGF; ft-1; KDR; flk-1; 肝星細胞; fet-1

The prognosis of fulminant hepatic failure is extremely poor in most cases of the patients, since impaired liver regeneration frequently develops. Sinusoidal endothelial cell injury is a major abnormal finding in the liver of such patients. Proliferation of sinusoidal endothelial cells seems to be essential for the progression of liver regeneration, since the cells play a role in the supply of blood flow to the injured liver. Vascular endothelial growth factor, VEGF, is shown to induce proliferation of cultured sinusoidal endothelial cells. Thus, VEGF expression was examined in rat liver following partial resection, injury and cold preservation to clarify the relation between sinusoidal endothelial cell proliferation and the development of impaired liver regeneration.In partially resected and injured liver, VEGF mRNA and protein were expressed increasingly in regenerating hepatocytes. Marked VEGE expression was also found in activated Kupifer cells, macrophages and stellate cells in th … More e necrotic areas of injured liver, However, activated sinusoidal cells induced proliferation of vascular endothelial cells leading to capillarization of the hepatic sinusoids, since they produced PDGF and basic FGF as well VEGE In contrast, VEGF derived from regenerating hepatocytes seems to be essential for the reconstruction of the hepatic sinusoids through proliferation of sinusoidal endothelial cells. Plasma VEGF concentration was measured serially in fulminant hepatic failure patients in whom the presence of impaired liver regeneration was suspected based on ultrasonography and/or CT scan. In all patients, VEGF was undetectable in their plasma, suggesting that sinusoidal endothelial cell proliferation was retarded in the patients complicated with impaired liver regeneration.VEGF expression was increased in hepatocytes in the liver following cold preservation in UW solution. In such liver, however, the expressions of VEGF receptors, fit-i and KDR/flk-1 , diminished preceding the occurrance of sinusoidal endothelial cell injury. The derangement in communication between VEGF and its receptors may be a factor respopsible for the development of such sinusoidal endothelial cell injury, as VEGF is a maintenance factor as well as a growth factor of the cells. When recombinant VEGF was added to the culture medium of endothelial cells, mRNA expressions of VEGF receptors increased in a dose-related manner, Thus, administration of recombinant VEGE may be effective for proliferation as well as protection of sinusoidal endotbelial cells in fulininant hepatic failure patients in whom hepatic microcirculatory disturbance develops Recently, we found that VEGF receptors were also expressed in hepatic stellate cells and VEGF can inhibit contraction of the ste1late cells during activation by culture, probably through attenuation of smooth muscle a actin expression via upregulated VEGF receptor, fit-1. Exogenous VEOF may attenuate microcirculatory disturbance in fulminant hepatic failure patients through inhibition of stellate cell contraction. Less

暴发性肝衰竭的预后在大多数情况下是非常差的患者，因为受损的肝再生经常发展。肝窦内皮细胞损伤是此类患者肝脏的主要异常发现。肝窦内皮细胞的增殖似乎对肝再生的进展是必不可少的，因为这些细胞在向损伤的肝供应血流中起作用。血管内皮生长因子（VEGF）可诱导培养的肝窦内皮细胞增殖。因此，我们检测了部分切除、损伤和冷保存后大鼠肝脏中VEGF的表达，以阐明肝窦内皮细胞增殖与肝再生受损发展之间的关系。在部分切除和损伤的肝脏中，再生肝细胞中VEGF mRNA和蛋白的表达增加。VEGE的表达在活化的Kupifer细胞、巨噬细胞和星形细胞中也有明显的表达。 ...更多信息 然而，激活的肝窦细胞诱导血管内皮细胞增殖，导致肝窦毛细血管化，因为它们产生PDGF和碱性FGF以及VEGF。相反，来自再生肝细胞的VEGF似乎是通过肝窦内皮细胞增殖重建肝窦所必需的。在根据超声和/或CT扫描怀疑存在肝再生受损的暴发性肝衰竭患者中，连续测量血浆VEGF浓度。所有患者血浆中均未检测到VEGF，提示肝再生受损患者肝窦内皮细胞增殖受阻，UW液冷保存后肝细胞VEGF表达增加。然而，在这样的肝脏中，血管内皮生长因子受体fit-1和KDR/flk-1的表达在肝窦内皮细胞损伤发生之前就减少了。VEGF与其受体之间的通讯紊乱可能是导致这种窦状内皮细胞损伤发展的因素，因为VEGF是细胞的维持因子以及生长因子。在内皮细胞培养液中加入重组VEGF后，VEGF受体mRNA表达呈剂量相关性增加。因此，在暴发性肝衰竭患者中，给予重组VEGF可能对肝微循环障碍的肝窦内皮细胞的增殖和保护有效。我们发现VEGF受体也在肝星状细胞中表达，并且VEGF可以抑制培养激活过程中星状细胞的收缩，这可能是通过上调VEGF受体fit-1减弱平滑肌α肌动蛋白表达。外源性VEOF可能通过抑制肝星状细胞收缩减轻暴发性肝功能衰竭患者的微循环障碍。少

项目成果

Arai S,Mochida S,Ohno A,et al.: "Decreased expressions of receptors for vascular endothelial growth factor and sinusoidal endothelial cell damage in cold preserved rat liver." Transplant Proc. 印刷中.

Arai S、Mochida S、Ohno A 等人：“移植过程中血管内皮生长因子受体表达减少和肝窦内皮细胞损伤。”

Mochida S,Arai S,Yamanobe F,et al.: "Anticoagulant targeting for hepatic sinusoidal walls in prevention of hypercoagulopathy in cold preserved rat livers." Transplant Proc. 30. 45-48 (1998)

Mochida S、Arai S、Yamanobe F 等人：“针对肝窦壁的抗凝剂可预防冷藏大鼠肝脏中的高凝病。”

Mashiba S,Mochida S,Ishikawa K,Inao M,Matsui A,Ohno A,Ikeda H,Nagoshi S,Shibuya M,Fujiwara K.: "Inhibition of hepatic stellate cell contraction during activation in vitro by vascular endothelial growth factor in association with uprgulation of FLT tyrosin

Mashiba S、Mochida S、Ishikawa K、Inao M、Matsui A、Ohno A、Ikeda H、Nagoshi S、Shibuya M、Fujiwara K.：“血管内皮生长因子与体外激活过程中肝星状细胞收缩的抑制作用

Mashimo Y,Mochida S,Inao M,Yamaoka M,Nagoshi S,Matsui A,Fujiwara K.: "Decreased expression of smooth muscle alpha actin in activated rat hepatic stellate cells at the S-phase of the cell cycle in vitro." Hepatology Res. (in press).

Mashimo Y、Mochida S、Inao M、Yamaoka M、Nagoshi S、Matsui A、Fujiwara K.：“体外细胞周期 S 期激活的大鼠肝星状细胞中平滑肌 α 肌动蛋白的表达减少。”

Mochda S,Ishiakwa K,Toshima K,Inao M,Ikeda H,Matsui A,Shibuya M,Fujiwara K.: "The mechanisms of hepatic sinusoidal endothelial cell regeneration : A possible communication system associated with vascular endothelial growth factor in liver cells." J Gastro

Mochda S，Ishiakwa K，Toshima K，Inao M，Ikeda H，Matsui A，Shibuya M，Fujiwara K.：“肝窦内皮细胞再生的机制：与肝细胞中血管内皮生长因子相关的可能的通讯系统。”