| Co-Investigator(Kenkyū-buntansha) |
YAMANOBE Fumio Saitama Medical School, Faculty of Medicine, Assistant, 医学部, 助手 (90286097)
INAO Mie Saitama Medical School, Faculty of Medicine, Assistant, 医学部, 助手 (70286037)
MATSUI Atsushi Saitama Medical School, Faculty of Medicine, Assistant, 医学部, 助手 (40260484)
FUJIWARA Kenji Saitama Medical School, Faculty of Medicine, Professor and Chairman, 医学部, 教授 (80101088)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 1998: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1997: ¥2,700,000 (Direct Cost: ¥2,700,000)
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| Research Abstract |
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
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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
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