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

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，VEGF的表达在大鼠肝脏部分切除，损伤和冷保存，以阐明窦内皮细胞增殖和受损的肝再生的发展之间的关系进行了检查。在部分切除和损伤的肝脏，VEGF的mRNA和蛋白表达在再生肝细胞增加。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。在肝窦内皮细胞损伤发生前，VEGF受体fit-1和KDR/flk-1的表达减少。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

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