硼替佐米调控泛素蛋白酶活性治疗小鼠重症急性胰腺炎的作用及其机制  

The therapeutic effect and mechanisms of PS-341 for the treatment of severe acute pancreatitis by modulating the ubiquitin-proteasome pathway

作　　者：詹银楚[1] 姜仁鸦[1] 吴善水[1] 余耀生[1] 胡雅国[1] 姚宏宇[1] 俞新春[1] 

机构地区：[1]浙江衢州市人民医院肝胆外科,324000

出　　处：《中华实验外科杂志》2011年第11期1932-1934,I0002,F0003,共5页Chinese Journal of Experimental Surgery

基　　金：浙江省科技厅资助项目（2006C33077）

摘　　要：目的探讨蛋白酶体抑制剂硼替佐米调控泛素蛋白酶活性治疗小鼠重症急性胰腺炎的作用机制。方法采用连续7次腹内注射雨蛙素（每次间隔1h）及脂多糖制作小鼠重症急性胰腺炎模型，将60只ICR雌性小鼠随机分为PS-341治疗组（注射脂多糖前0．5h腹内注射0．5mg／kg PS-341）、模型对照组[注射脂多糖前0．5h腹内注射50％二甲基亚砜（DMSO）]、空白对照组（生理盐水制模）。最后1次注射雨蛙素后2h麻醉小鼠，自右颈静脉取血检测血淀粉酶、白细胞介素（IL）-1β和IL-6。光镜下观察小鼠胰腺、肺脏的病理形态，应用TUNEL法检测细胞凋亡，免疫印迹法（Western blot）检测胰腺组织中IKBoL的表达，电泳迁移率实验（EMSA）测定核因子（NF）．KB活性。结果雨蛀素联合脂多糖小鼠腹腔内注射后，小鼠胰腺呈现典型的出血、坏死病理表现，血清淀粉酶、IL-1B、IL-6的表达值分别为：7663．0±559．0、229．6±41．0、51．6±10．3，都较空白对照组（1732．0±540．0、9．3±1．8、4．3±1．0）明显升高（P〈0．05）。PS-341治疗后，胰腺组织中I—κB降解自3．37±0．46减少至2．48±0．57，NF—κB活性自7．82±0．45下降至2．13±0．26，胰腺和肺脏出血、坏死和炎细胞浸润明显减轻；血清淀粉酶、IL-1B、IL-6的表达（2927．0±524．0、153．3±30．4、37．9±7．5）都较对照组显著下降；而胰腺组织中细胞凋亡明显增多（4．35±0．19增至7．91±0．26，P〈0．05）。结论PS-341可以抑制胰腺内NF—κB活化、促进细胞凋亡，从而减轻胰腺损伤，对小鼠重症胰腺炎有一定的治疗作用。Objective To observe the effect of PS-341 on nulear factor （NF）-KB activation in mice with severe acute pancreatitis. Methods Severe acute pancreatitis was induced by cerulin and li- popolysaccharide （LPS） in mice. 30 minutes before the administration of lipopolysaccharide, mice were treated either PS-341 or vehicle. Blood samples were collected from right jugular veins for the serum amylase, interleukin （IL）-1β and IL-6. Pancreatic inflammation and the acinar cell apoptosis were assessed. Pancreatic expression of I-κB was measured by Western blotting analysis and the activation of NF-κB was assessed by electrophoretic mobility shift assay. Results Injection of cerulein and lipopolysaccharide induced severe acute pancreatitis, the serum amylase, IL-113 and IL-6 concentrations were significantly elevated （7663.0 ±559. 0, 229, 6 ±41.0, 51.6±10. 3）, histological investigation revealed pancreatic interstitial edema. PS-341 treatment significantly inhibited NF-κB activation （from 7. 82 ±0. 45 to 2. 13 ±0. 26）, while the acinar cell apoptosis was significantly enhanced （from 4. 35 ±0. 19 to 7. 91 ±0. 26）, resulting in the improved parameters such as serum amylase, interleukin-ll3 and interleukin-6 （2927.0 ± 524. 0, 153.3 ±30. 4, 37.9±7.5 ）. Accordingly ,the pancreatic damage was also markedly reduced. Conclusion PS-341 may be a promising drug to prevent disease progression in severe acute panereatiits by inhibition of NF-κB activation and increased acinar cell apoptosis within the pancreas.

关 键 词：重症急性胰腺炎 蛋白酶体抑制剂 核因子-ΚB 凋亡 

分 类 号：R576[医药卫生—消化系统]