Effect Of PPAR-α Agonist Pirinic Acid On Oxidative Stress In Liver Tissues Adjacent To Hepatocellular Carcinoma After TAE

Objective:To investigate the effect of peroxisome proliferator-activated receptor alpha（PPAR-α）agonist-pirinixic acid（WY14643）on oxidative stress and injury to the para cancerous liver tissue and its mechanism of protection of hepatic function after transcatheter arterial embolization（TAE）in VX2 liver cancer rabbit models.Methods:A total of twenty-four（24）rabbit VX2 liver cancer models were established and were randomly divided into three groups consisting of eight（8）rabbits in each group as the control group;the TAE group;the combined treatment group（TAE surgery+pirinixic acid intervention）respectively.In the combined treatment group,3mg/kg·d of pirinixic acid and 8 ml/kg·d of 10%dimethyl sulfoxide（DMSO）bolus was injected through the periauricular vein simultaneously for 3 days before TAE intervention;the control group and TAE group were injected with an only corresponding dose of 10%DMSO through the periauricular vein.The TAE group and the combined treatment groups underwent transarterial arterial embolization（TAE）,and the feeding arteries of the tumor were selectively embolized with ethiodol oil（0.15ml/kg）.The control group did not undergo any treatment.Venous blood was collected simultaneously 3 days before and 3 days after TAE from all the rabbits;liver function parameters like alanine aminotransferase（ALT）and aspartate aminotransferase（AST）were measured in the peripheral blood using chemical colorimetry.All the rabbits were euthanized on the 3^rd day after TAE.Samples from tumors along with para cancerous tissue（tissue more than 1 cm around tumors）were carefully excised,stored and fixed accordingly.The corresponding pathological changes in each tissue sample were carefully analyzed on Hematoxylin and Eosin（HE）staining;the levels of superoxide dismutase（SOD）,glutathione peroxidase（GSH-PX）,and catalase（CAT）were detected by using spectrophotometric assay respectively.SPSS 22.0 software package was used for statistical analysis.The measurement data were expressed as mean±standard deviation（±s）.The comparison of the three groups was performed by one-way ANOVA.The LSD-t-test was utilized for multiple comparisons between groups compare assuming homogeneity of variance.P<0.05 was considered to be statistically significant.Results:（1）Liver function parameters were analyzed on the fully automated biochemical analyzer.The results were as following:the levels of ALT and AST before TAE intervention did not show any significant statistical differences in all the groups（P>0.05）;however,after TAE intervention,the levels of ALT and AST in the combined treatment group were higher than that of control groups,while the parameter levels in TAE group were also higher than that of combined treatment group showing significant statistical differences（P>0.05）.（2）HE staining of samples of cancerous and para cancerous liver tissues of the TAE group showed prominent necrotic tissue and structural disintegration of the cells.A large number of inflammatory cell infiltration was also observed in this group.In the combined treatment group,structural disintegration of some hepatocytes along with inflammatory cells infiltration was observed in some hepatocytes.（3）Spectrophotometric assay analysis was used to detect oxidative stress in the para cancerous tissue.The SOD levels in the control group,TAE group,and combined treatment group were 46.64±1.53（U/mgprot）,21.69±1.24（U/mgprot）,and 66.49±1.89（U/mgprot）respectively.The GSH-PX levels are264.51±5.07（U/mgprot）,188.45±4.69（U/mgprot）,and 313.34±5.57（U/mgprot）,and CAT levels are 3.32±0.37（U/mgprot）,1.29±0.23（U/mgprot）,and 5.54±0.37（U/mgprot）respectively.Compared with the control group,the activity of SOD,GSH-PX and CAT in the TAE group model rabbits was reduced and showed significant statistical differences（P<0.05）;Compared with the TAE and the control groups,the activity of SOD,GSH-PX and CAT indicators in the combined treatment group were significantly increased,and the differences were statistically significant（P<0.05）.Conclusion:It has been observed that oxidative stress has indeed occurred in the para cancerous tissues as the adjacent healthy hepatocytes were damaged,thereby,showing a greater impact on the liver function.This study shows that pre-administration of PPAR-αagonist-pirinixic acid may activate the expression of PPAR-αin hepatic parenchymal cells,which regulates the production of enzymatic antioxidant factors,thereby inhibiting the oxidative stress response of liver tissues in the para cancerous tissues after TAE intervention and,thereby significantly reducing the collateral liver injury induced after TAE.Based on these results,we can infer that the use of PPAR-αagonist pirinixic acid to activate PPAR-αbefore selective embolization intervention can remarkably prevent and in fact reduce the resultant liver damage after TAE treatment.