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病例中是非常差的，因为肝再生受损经常发生。肝窦内皮细胞损伤是这类患者肝脏的主要异常发现。窦状内皮细胞的增殖似乎对肝脏再生的进展至关重要，因为这些细胞在向受损肝脏供应血液方面起着重要作用。血管内皮生长因子（VEGF）可诱导培养的血管内皮细胞增殖。因此，我们在部分切除、损伤和冷保存后的大鼠肝脏中检测VEGF的表达，以阐明肝窦内皮细胞增殖与受损肝再生发展的关系。在部分切除和损伤的肝脏中，VEGF mRNA和蛋白在再生肝细胞中的表达增加。激活的Kupifer细胞、巨噬细胞和星状细胞中也发现了明显的vegf表达，损伤肝脏的坏死区域更多。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。来源于再生肝细胞的VEGF似乎是通过肝窦内皮细胞增殖重建肝窦所必需的。在基于超声和/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血管内皮细胞增殖迟缓。在UW溶液中低温保存后，肝细胞中VEGF表达增加。然而，在这种肝脏中，血管内皮生长因子受体fit- 1和KDR/flk-1的表达在血管内皮细胞损伤发生前减少。VEGF既是细胞的维持因子，又是细胞的生长因子，因此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生的一个因素。在内皮细胞培养液中加入重组VEGF后，VEGF受体mRNA表达呈剂量相关增加，提示重组VEGF可能对出现肝微循环障碍的急性肝功能衰竭患者的窦状内皮细胞增殖和保护有一定作用。我们发现VEGF受体在肝星状细胞中也有表达，并且在培养过程中，VEGF可以抑制星状细胞的收缩，可能是通过上调VEGF受体fit-1来抑制平滑肌a肌动蛋白的表达。外源性VEOF可能通过抑制星状细胞收缩来减轻暴发性肝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