JAK/STAT通路介导脓毒症大鼠肝组织高迁移率族蛋白B1 mRNA表达的研究

Role of Janus kinase/signal transducer and activator of transcription pathway in mediating mRNA expression of high mobility group box1 protein in the liver in septic rats

目的 :探讨 Janus激酶 /信号转导和转录激活子 ( JAK/ STAT)通路对盲肠结扎穿孔术 ( CL P)所致脓毒症大鼠肝组织高迁移率族蛋白 B1( HMGB1) m RNA表达和急性肝损害的影响。方法 :采用 CL P模型 ,大鼠随机分为正常对照组、CL P脓毒症组、JAK2激酶抑制剂 AG490和 STAT抑制剂雷帕霉素 ( RPM)处理组。采用逆转录多聚酶链式反应测定肝 HMGB1m RNA,全自动生化分析仪测定肝功能指标。结果 :与正常对照组相比 ,CL P后 6～ 48h HMGB1m RNA表达显著升高 ( P<0 .0 1) ;血清天冬氨酸转氨酶 ( AST)在 6～ 48h增高明显( P<0 .0 5 ) ,丙氨酸转氨酶 ( AL T)、 AST在 2 4h升高非常显著 ( P<0 .0 1)。与 CL P组相比 ,AG490预处理组2 4h HMGB1m RNA和 AL T水平显著下降 ( P均 <0 .0 1) ,2 4h和 48h AST亦明显降低 ( P均 <0 .0 1) ;同样 ,RPM干预后 HMGB1m RNA表达在 6 h和 2 4h显著抑制 ( P<0 .0 5和 P<0 .0 1) ,AL T、AST在 2 4h和 48h均不同程度下降 ( P<0 .0 1和 P<0 .0 5 )。结论 :抑制 JAK/ STAT通路活化可明显下调肝组织 HMGB1m RNA表达 ,并有助于减轻 CL P所致急性肝损伤。

Objective:To investigate the role of Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway in mediating mRNA expression of high mobility group box1 protein (HMGB1) in the liver in septic rats.Methods:Using a sepsis model of cecal ligation and puncture (CLP),98 male Wistar rats were randomly divided into normal control group (n=10),CLP group (n=40),AG490 treatment group (n=24),and Rapamycin (RPM) treatment group (n=24).At serial time points animals in each group were sacrificed,and blood as well as hepatic tissue samples were harvested to determine HMGB1 mRNA expression and serum aspartate aminotransferase(AST) as well as alanine aminotransferase(ALT) contents.Results:Compared with normal controls,HMGB1 mRNA levels were significantly increased in the liver during 648 hours after CLP (P<0 01),and serum AST and ALT contents were significantly elevated at different time points respectively (P<0 05 or P<0 01).Treatment with AG490 and RPM could markedly inhibit HMGB1 mRNA expression in the liver at 24 hours,48 hours,6 hours and 24 hours after CLP,respectively.In addition,compared to CLP group,serum AST and ALT contents in both treatment groups could be markedly reduced at various intervals after CLP (P<0 05 or P<0 01).Conclusion:These data suggest that the activation of JAK/STAT pathway might be involved in mediating upregulation of HMGB1 mRNA expression in the liver in CLPinduced sepsis.Treatment with inhibitors of JAK/STAT pathway could markedly downregulate HMGB1 mRNA expression and attenuate acute liver injury associated with sepsis.