Effects Of VEGF On The Liver Function And Liver Regeneration Of Rats Following Partial Liver Transplantation

Liver transplantation has become the ultimate effective therapia for end stage liver dieases. The deficient supply of donator liver, however, has become the major agent to restric the development of livertransplantation. To meet this problem, the living donor tecthnic, with transplantation of liver segments, have been carried out promptly. But many problems, such as the activity of recipient graft, the matching to recieper and liver function failure after operation, are to be solved. The liver function failure of graft has been a most important agent that decide therapeutic efficacy of liver transplantation, and witch concerned with liver ischemical reperfusion injury and the suffering activity of liver regeneration besides immunization rejection and nutritic agents.Liver regeneration has been attributed to hepatocyte proliferation following different kind of injury, reflecting the priming of G0 cells and shift to G0 to the G1/S, accompanied by changes of gene expression and hormone secretion. Once the renovation completed, the proliferation circulation quit. The procedure of liver is very complic, which include the heaptocytes and nonparenchymal cell and its secretion of a large numberof cytokines. First of all , the growth factors, produced by nonparenchymal cell (LSEC,and Ito's cell Kupffer cell), is proved to be the mitogen which promtes hepatocyte shift from G1 to S. Il-6 is proved to be a indispensable mediator produced majorly by nonparenchymal cell in liver and intestinal gland。The liver regeneration procedure after partial liver transplantation is more complicate and specialer, on the one hand ,the liver regeneration was prompted by the loss of liver tissue ,on the other hand the liver sindusoial endothelial cells were injuried by liver ischemical reperfusion injury, accompanied with liver microcirculation disturbance and hepatic parenchymal cells injury because of cellularedema and platelet leucocyte adhesion. And the injury of LSEC has been a major agent which effect the activity of liver regeneration, because the LSEC is the"inducer"of liver regeneration, HGF/IL-6 and TNF-a,NO secreated by LSEC after liver Partial excision can priminted and enhance hepatocytes proliferation. It is very important to improve liver function and enhance the activity of liver regeneration after liver transplantation that to find the injury of LSEC and givie effective therapy .Vascular endothelial growth factor(VEGF), a potent angiogenic factor, can improve blood vessel endothelium cells hyperplasy, and it has been proved that can promote sinus hepaticus hyperplasy and suppress its apoptosis vitro. VEGF can enhance liver regeneration after partial hepatectomy. Recently study indicated that VEGF can relieve acute severe liver injury(ALI) induced by chemical factor, VEGF treatment significantly reduced the mortality rate of ALI in the rat, and it may provide a new therapeutic strategy for ALI. It was reported that hyperbaric oxygen treatment significantly reduced the liver function damage,and enhance the proliferation of hepatocytes and LSECs ,meanwhile the hyperbaric oxygen treatment significantly increased the expression of VEGF protein in the regenerating liver .Can VEGF improve LSEC function or decrease liver ischemical reperfusion injury? Up to now there are few reports .The role of the phosphoinositide 3-kinase/Akt-signal pathway is very important on differentiation, migration, proliferation and anti-apoptosis, invasion, Angiogenesis. Akt is the downstream target protein of PI3K,and bring into it's full biological effect after activated by PI3K.Activated Akt stimulates liver stella cells proliferation under no serum condition. Blockage of the expression of Akt can suppress liver stella cells proliferation evoked by platelet-derived growth factor. Akt can accommodate the activity of nitric oxide synthase, and increase the synthesis of nitric oxide, and inhibit platelet aggregation and its combining with hyperoxide, and prevent hepatocytes from damage caused by oxygen free radical. Can VEGF activate Akt of LSEC? Up to now there are few reports.This study identified that VEGF can improve hepatic function and promote liver regeneration by observation the effects of VEGF on the functional biochemistry, the level of hyaluronic acid , the morphous of LSECs, and the expression index of proliferating cell nuclear antigen of hepatocytes of rat following partial liver transplantation. To explore the mechanism of effects of VEGF on improving Liver function, degrading ischemical reperfusion injury, and enhancing the activity of heaptocytes proliferation, we observed the effects of VEGF on the levels of HGF, Il-6, and the expression of HGF mRNA and Akt of LSEC after rat partial liver transplantation. This may provide a new therapy strategy for hepatic inadequacy after for-small-size partial liver transplantation for clinical.In this project we explore the role of VEGF in partial liver transplantation, the results are followed:1. A stabile animal model of rats serial reduced-size liver transplantation were set up and the effect of ratio of rat liver graft on liver function and survival rate were evaluated. This provides a experiment foundation for exploring liver regeneration after partial liver transplantation2. To identify that exogenous VEGF can improve the LSEC function,low down liver ischemical reperfusion injury, and elevate the survival rate of rats subjected partial liver transplantation. This may provide a new clinical treatment strategy for hepatic inadequacy after reduced-size liver transplantation.3. Our experiment show that VEGF can enhance the secretion of HGF, IL-6 by activated LSEC through Akt phosphorylated pathway and promote liver regeneration after partial liver transplantation.