| Objective:To improve the bad hepatocellular microenvironment of inflammatory response，to antagonize exaggerated inflammatory response and to protect functionally residualhepatocyte by using AG490to idiocratic inhibit JAK-STAT pathway. Meanwhile,using exogenous VEGF induced liver regeneration and the proliferation of liversinusoidal endothelial cells. Based on these, we try to crystallize the molecularmechanisms of our treatment and provide the fundational reference for preventionand cure hepatic failure after expanded hepatectomy.Mathods:We used SD rats to build acute hepatic failure models after expandedhepatectomy. These models were randomized intofour groups, each of which hasA=15, B=35,C=25,D=45rats. We adminitered medicine to all the rats at0hour、12hour,24hour,36hour after hepatectomy. Our study focused on the generalcondition,survival time,survival rate,the function of residual hepatocyte and liverregeneration after surgery,meanwhile,the expression of Il-6,Il-10,phosphorylate JAK2and Stat3.The four groups: group A:treated with VEGF and AG490;group B,treated withVEGF;group C,treated with AG490; group D: were the control group. The dose androute of administration:AG490:1mg/kg, intraperitoneal injection;VEGF:100ng/eachrat,caudal vein injection.Results:1. The survival time of four groups was78.9±5.7h，89.2±7.0h，73.0±4.8h108.0±6.2h respectively. Compared group A with group B and D, the difference ofsurvial time was statistically significant, demonstrating AG490can prolong thesurvival time and impove outcomes.2. All rats in our study survived within12h after hepatectomy. The survival ratebegan to decrease after24h. When120h after surgery, the survival rate of four groups decreased to80%,28.6%,44%,20%respectively. Based on our study, demonstratedAG490moderated inflammatory response and improved survival rate.3. Diffuse degeneration of residual liver was observed when we opened the rats’abdomen. We observed the pathological change of residual hepatocyte after surgeryat24h and48h respectively. Hepaticsinusoidal was enlarged, hepatocytes werevacuolated and focal or spotty necrotic after24h. With the progress of hepatic failureand inflammatory response,hepatocytes were piecemeal necrotic andhepaticsinusoidal was obvious enlarged. Immunohistochemical staining of residualhepatocyte present the clear regeneration of hepatocytes after postoperative48h.4. We tested the rate of liver regeneration at24h,48h,72h,120h respectively.Comparing group A and other groups, the difference was statistically significant,sepecially at72h after surgery. The rate of liver regeneration began to increase at24hafter surgery, then reached to peak at72h, while the tendedncy consisted with PCNA.5. ALT、AST、Tbi1representing liver function began to increase after surgery，then reached to peak and fell slowly. Comparing group A with other groups, between8h-120h, the differencese of these three indexes were statistically sifnificant,particularly at24h. Beside, comparing group B and D,ALT,AST,Tbi1tended tonormal. These results demonstrated both AG49and VEGF improved liver functionand bile secretion, thus protected hepatocyte..6. The expression of Il-6and IL-10was unimodal distributed, which group A andC reached to peak at24h, comparing group B and D at48h. The inflammatoryresponse from group A was weaker than other groups, representing AG490canantagonize inflammatory response.7. We detected the expression of Jak2and Stat3at12h,24h,72h,120h aftersurger, which reached to peak at24h. Compared group A and other groups, thedifference was statistically significant. Our study showed AG490and VEGFinterfered the expression of Jak2and Stat3.Conclusion:1. Exogenous VEGF improved the liver regeneration and raise postoperativesurvival rate.2. AG490downgraded the expression of IL-6, Jak2, Stat3, thus antagonized inflammatory response and elevated postoperative survival rate.3. AG490and VEGFcombination treatment improved the repair andregeneration of hepatocyte. |
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