The Regulatory Effect Of YAP On Inflammatory Factors In Anti-tuberculousis Drug-induced Liver Injury

Objectives This study aims to investigate the regulatory effect of Yes-associated protein(YAP)in anti-tuberculosis drug-induced liver injury(ADLI)on NLRP3 inflammasome pathway.Methods This study carried out a population survey and animal experiments.1 Crowd investigation: The clinical data of hospitalized patients with pulmonary tuberculosis who were first diagnosed in the Fifth Hospital of Shijiazhuang from January 2019 to January2020 and blood samples at different follow-up time points were collected.The 103 patients included in the study were divided into ADLI group and non-ADLI group.Statistical software SPSS was used to analyze the collected clinical data;Non-parametric test or independent sample t test was used to analyze whether the m RNA and protein levels of ALT,AST,YAP,NLRP3,IL-1β and caspase-1 were different between ADLI group and nonADLI group at the same time point.Non-parametric test or repeated measurement variance analysis was used to test whether the m RNA and protein dynamic expression levels of ALT,AST,YAP,NLRP3,IL-1β and caspase-1 were different in ADLI group or non-ADLI group.At the protein level,pearson product moment correlation were used to analyze the correlation between YAP and NLRP3 and ALT,AST and the correlation between YAP and NLRP3.2Animal experimental study: 180 Kunming mice were randomly divided into 6 groups: blank control group,blank solvent group,blank inhibitor group,drug group,drug solvent group,drug inhibitor group.The mice were sacrificed after 7 days of intragastric administration.The expression levels of ALT and AST in serum were detected by microplate method to determine whether liver injury occurred.HE staining was used to observe the pathological changes of liver tissue;The m RNA levels of YAP,NLRP3,IL-1β and caspase-1 in serum and liver tissues were detected by real-time fluorescence quantitative PCR.The expression levels of YAP,NLRP3,IL-1β and caspase-1 in serum and liver tissues were detected by ELISA.Results 1 Crowd investigation: From the dynamic changes of T1,T2 and T3,the m RNA and protein expression levels of YAP in serum of ADLI group increased significantly one week after administration,and decreased rapidly one week after administration of hepatoprotective drugs,but the dynamic changes in serum of non-ADLI group were not obvious(P > 0.05).The dynamic change trend of ALT and AST in serum of patients in ADLI group was consistent with that of YAP,indicating that the change of YAP was related to the degree of liver injury.The dynamic changes of m RNA and protein expression of NLRP3,IL-1β and caspase-1 in the serum of the two groups were consistent with the change trend of YAP,suggesting that these indexes were correlated with YAP.The YAP protein in the serum of patients was positively correlated with the protein expression levels of ALT,AST and NLRP3,and the expression level of NLRP3 protein was also positively correlated with ALT and AST(P < 0.05).At T2 and T3,the m RNA and protein expression levels of YAP,NLRP3,IL-1β and caspase-1 were significantly higher than those in the non-ADLI group(all P < 0.05),indicating that the changes of these indicators were closely related to the degree of liver injury.The use of hepatoprotective drugs can effectively reduce druginduced liver injury.2 Animal experimental study: Compared with the blank control group,the serum ALT and AST levels of the drug group,the drug solvent group and the drug inhibitor group increased,reaching the standard of liver injury.The pathological results of the drug group,the drug solvent group and the drug inhibitor group showed hepatocyte apoptosis and necrosis,that is,the model was successfully established.Compared with the drug group,the levels of ALT and AST in the drug inhibitor group were decreased(P <0.05),and the liver injury in the drug inhibitor group was improved.Compared with the blank control group,the m RNA levels of YAP,NLRP3,IL-1β and caspase-1 in serum and liver tissue of mice in the drug group were increased,while those in the drug group were decreased after the use of inhibitors(all P < 0.05).The results of serum protein YAP,NLRP3,IL-1β and caspase-1 were consistent with those of m RNA(all P < 0.05).The expression of YAP protein in liver tissue was consistent with that in serum(P < 0.05).The use of inhibitors can effectively reduce the expression of YAP and NLRP3 inflammasome.Conclusions 1 YAP and NLRP3 inflammasome related factors are up-regulated in antituberculosis drug-induced liver injury.2 Inhibition of YAP can down-regulate the expression level of NLRP3 inflammasome pathway and alleviate liver injury.Figure 10;Table 12;Reference 162...