| Backgrounds and Objective: With the improvement of liver surgical techniques,the development of equipment and medical materials,liver surgery plays an increasingly important role in the treatment of various benign and malignant liver diseases.Liver surgery is currently available for a wider range of surgery which is more difficult and dangerous.After effective and safe operations,patients also need more ideal drug treatment to ensure the successful recovery.As an artificially synthesized vasopressin analogue,Terlipressin can selectively contract the gastrointestinal capillary bed to reduce the pressure of the portal vein.It has a good effect on some common complications of cirrhotic portal hypertension.Recently,Terlipressin can significantly improve liver function after subtotal liver resection,and can reduce the incidence of small liver syndrome and even liver failure.It is also reported that Terlipressin can promote the regeneration of residual liver by reducing the high portal vein pressure after liver resection.The purpose of this study is to explore the role and mechanism of Terlipressin in hepatocyte regeneration after subtotal hepatectomy.Research Methods: The statistical results of clinical data were: the liver function indexes with statistically significant difference on the first day after the operation were: ALT(group 1:188.71±136.22 VS group 0:444.43±290.40)(P=0.004);AST(group 1:377.76±147.56 VS group 0:648.67±421.07)(P=0.009);PT(group 1:13.41±1.47 VS group 0:14.76±1.54)(P=0.028);TB(Firstly,a retrospective cohort study was conducted including 42 patients who received partial hepatectomy from November to December of 2016 and from May to December of 2017 in the special treatment/ liver transplantation department of Eastern Hepatobiliary Surgery Hospital,Shanghai,China.21 patients who were treated with terlipressin after surgery were enrolled in the drug treatment group while the other 21 patients who were not treated with terlipressin were enrolled in the control group.The liver function of the patients between the two groups at the first day and the third day after surgery were compared.Secondly,postoperative 4 time points(24 hours,48 hours,72 hours and 96 hours)were selected to compare the liver regeneration condition in the mouse subtotal liver resection model between terlipressin group and placebo group.Then,the mouse liver specimens were detected by gene expression spectrum chip to explore the possible mechanism of vasopressin in remaining hepatocyte regeneration after partial hepatectomy.Furthermore,HL7702 cells were applied in vitro experiments.The cells cultured in the medium added vasopressin were treated as the experimental group,while the cells cultured in the common medium were treated as the control group.CCK8 was used to compare the relative growth rate of cells of different groups.Cell cycle detection was performed by flow cytometry.Finally,PCR was used to verify the possible mechanism screened by gene expression spectrum chip.Research Results: The statistical results of clinical data showed that the liver function indexes with significant difference on the first day after the operation were: ALT(Terlipresin group:188.71±136.22 VS control group:444.43±290.40,P=0.004);AST(Terlipresin group:377.76±147.56 VS control group:648.67±421.07,P=0.009);PT(Terlipresin group:13.41±1.47 VS control group:14.76±1.54,P=0.028);TB(Terlipresin group:22.79±11.44 VS control group:37.35±19.14,P=0.008)?The liver function indexes with significant difference on the third day after the operation were: ALT(Terlipresin group:166.24±96.91 VS control group:273.62±133.89,P=0.025);TB(Terlipresin group:33.92±18.71 VS control group:45.19±24.61,P=0.008);ALB(Terlipresin group:40.10±3.40 VS control group:37.12±2.55,P=0.002);PA(Terlipresin group:88.57±27.71 VS control group:57.00±20.56,P=0.000);PT(Terlipresin group:13.67±0.98 VS control group:15.35±1.87,P=0.003).The statistical results of the mouse subtotal liver resection model showed that the liver weight of terlipressin group at the points of the 24 hours(Terlipresin group:0.02533±0.000577 VS placebo group:0.01667±0.002082,P=0.002)and 48 hours(Terlipresin group:0.02881±0.004116 VS placebo group:0.02174±0.000659,P=0.043)after the operation was significantly higher than that of the control group.In the 48 hours after the operation,the mitotic figures of the terlipressin group were much more than that of the control group(Terlipresin group:31.33±2.082 VS placebo group:20.67±1.528,P=0.002).The positive rate of Ki 67 staining of the terlipressin group was also significantly higher in the 24 hours(Terlipresin group:30.1%±0.42 VS placebo group:8.57%±1.06,P=0.0001)and 48 hours(Terlipresin group:42.14%±4.92 VS placebo group:9.42%±1.11,P=0.012)after surgery.42.14%±4.92? 9.42%±1.11,(P=0.012)?The serum HGF of the terlipressin group was also significantly higher in the 24 hours(Terlipresin group: 3663.35±200.86 VS placebo group: 1936.77±394.22 pg/ml,P=0.002)and 48 hours(Terlipresin group: 532.80±65.38 VS placebo group: 274.68±19.46pg/ml,P=0.003)after surgery.The results of gene chip showed that the high multiplication gene in the terlipressin group was mainly related to cell cycle.The CCK8 detection value of the 96 hours in the terlipressin group was significantly higher than that in the control group,the population doublings were 6.28±0.18 and 5.46±0.01 respectively(P=0.009).Cell cycle analysis via flow cytometry showed that the proportion of cells in the S phase in the terlipressin group was significantly higher than that in the control group(25.19% vs 17.55%).RT-PCR also confirmed that the expressions of Cyclin B1 and CDC20 remarkably increased in the terlipressin group after 24 hours and 48 hours of treatment with terlipressin than that in the control group.Cyclin B1 after 24 hours were 2.82±0.08 vs 1.00±0.04(P=0.001)and after 48 hours were 3.11±0.06 vs 1.00±0.03(P=0.001).CDC20 were 3.27±0.07 vs 1.00±0.03(P=0.001)after 24 hours and 3.89±0.03 vs 1.00±0.05(P=0.000)after 48 hours.Conclusions: Vasopressin can accelerate the recovery of residual liver function in patients and promote the regeneration of residual liver in mice after partial hepatectomy.It can also promote the proliferation of HL7702 cell line.The possible mechanism is realized through upregulating the expression of Cyclin B1 and CDC20 genes. |
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