| Chapter1.Animal trail:The effects and mechanism of survival rate by specific inflammatory signal inhibitor in rats following extensive liver resectionExtensive liver resection,if followed by fulminant liver failure,has a high mortality(70%～90%).It has long been an unsolved issue to find an effective way to protect and promote the function of residual liver to achieve a better survival.This is a first report concerning the effects of specific inflammatory signal inhibitor AG490 and P21-RAS inhibitor atorvastatin in the extensive liver resection(90%partial hepatectomy,90%PHx).Objective:Rat 90%hepatectomy was used as model for human extensive liver resection.Observe the effects of P21-RAS inhibitor atorvastatin and cytokine signaling inhibitor AG490 upon general situation,survival time,survival rate, liver regeneration,and liver functions.The possible biomolecular mechanism was also under investigation.Methods:Rats were divided randomly into three groups after surgery:Ctrl Group:given normal saline 1ml intraperitoneally,immediately and every 12 hours after the operation,till death occurred;Ator Group:administrated with atorvastatin(20mg·kg-1·d-1)through NG tube,one day before and three days after the surgery;AG490 Group:given AG490(1mg·kg-1·12h-1)intraperitoneally,immediately and through 36 hours after the operation.The survival situation,liver regeneration,and liver functions of the rats were observed and recorded.Efforts were also made to detect the phosphorylation of signal proteins Jak and Stat.Results:The rats in the Ctrl Group had 100%mortality rate within 24 hours. Severe damage to the residual hepatocytes was observed by pathological examinations.Both atorvastatin and AG490 significantly increased the survival time of rats after surgery(25.6 h & 30.6 h vs.10.7 h,p＜0.05), especially did the latter.The ratio of survival rate for the Ctrl Group and the AG490 Group was 0%vs.25%.Although atorvastatin increased the survival time,it did not improve the survival rate.None of the rat in the Ator group survived beyond 3 days.During the first 48 hours postoperatively,the remaining liver had started regeneration,which,however,seemed insufficient to compensate its function. Rats who survived up to one week,had regenerated livers heavier than half of their original weight.According to the results of Liver Regeneration Rate (LRR)and hepatocyte Proliferating Cell Nuclear Antigen(PCNA)counting, liver regeneration peaked at the post-operation-time(POT)72h.Although the regeneration was already obvious at POT 48h,little compensatory effects of the regeneration was observed.The AG490 Group had significantly better serum glucose and aminotransferase levels,and serum bilirubin levels decreased rapidly by 48 hours after the operation,when compared with the Control Group.Serum protein levels in both groups decreased slowly,without significance between each other.Conclusions:(1)During the first 48 hours after extensive liver resection,residual liver regeneration is insufficient to compensate for its former liver functions.Death can be resulted from the severe injury to the residual liver caused by various harmful factors,especially the overwhelming inflammatory response.Thus effective measures should be taken to help the residual liver out of this dangerous period of time.(2)It is the first report domestically and internationally to describe that the cytokine signaling inhibitor AG490 significantly increase the survival rate of rats following extensive liver resection.Atorvastatin also significantly prolonged the survival time.The damage towards residual hepatocytes caused by inflammatory response following extensive liver resection is much more serious than we used to consider.The result we obtained implies the theoretical basis of clinical application of certain curations and medications in the future.(3)The partial mechanisms were also studied in this experiment.Rats in the AG490 Group have better liver functions than those in the Control Group, which mainly benefits from protection towards the residual liver,rather than promotion of liver regeneration.The level of blood sugar in early stages is sensitive,which could be important for the prognosis of extensive liver resection.Chapter2.Clinical trail:The effects and mechanism of Ulinastatin following a prospective research in different liver resectionObjective:To investigate the effect of Ulinastatin,a urinary trypsin inhibitor on the outcome of patients undergoing liver resection,including the role and mechanism of inflammatory media and oxidation reaction based on a prospective,randomized,controlled clinical trail.Methods:In this clinical study,42 patients undergoing hepatectomy were randomly divided into Treatment group and Control group.In treatment group Ulinastatin was given on the day of surgery and the three consecutive days. Blood of thirty cases was tested for biochemistry.The levels of CD4,CD8, CRP,and gene expressions of IL-1,Il-6,TNF-alpha,iNOS were measured in blood sample of all patients.Results:Serum ALT and AST levels in treatment group were significantly lower than those in control group 12 hours post-operation,especially in patients undergoing multisegmentectomy.Difference became insignificant at the time point of 60 hours post-operation.Administration of UTI resulted in faster decrease of serum bilirubin level in patients undergoing small volume hepatectomy,and no effect on coagulative function was observed.The TNF-alpha and iNOS levels were significantly lower in the Treatment Group than in the Control Group 12 hours after surgery.The plasma peak of IL-1 was postponed by the administration of UTI.There was no significant change in CD4,CD8,and CRP within these two groups.Conclusions:The protective effects of urinary trypsin inhibitor exist mainly in early stage of major liver resection.The mechanism of protection role of UTI may via the inhibition and regulation of certain pro-inflammatory cytokines,which may also be related to the anti-oxidation effects.
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