沈昀泰,陈德喜,臧英,关鸽,刘欢,臧运金.Sigma-1受体在小鼠肝缺血再灌注损伤中的表达和作用[J].转化医学杂志,2019,8(6):321-325
Sigma-1受体在小鼠肝缺血再灌注损伤中的表达和作用
The expression and significance of Sigma-1 receptor in mouse liver ischemia reperfusion injury
  
DOI:
中文关键词:  Sigma-1受体  肝缺血再灌注损伤  炎症  小鼠
英文关键词:Sigma-1 receptor  Liver ischemia reperfusion  Inflammation  Mice
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作者单位
沈昀泰 山东 青岛青岛大学附属医院器官移植中心 青岛大学 
陈德喜 北京北京市肝病研究所 
臧英 山东 青岛青岛大学附属医院器官移植中心 青岛大学 
关鸽 山东 青岛青岛大学附属医院器官移植中心 
刘欢 山东 青岛青岛大学附属医院器官移植中心 青岛大学 
臧运金 山东 青岛青岛大学附属医院器官移植中心 青岛大学 
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中文摘要:
      目的 研究Sigma-1受体在小鼠肝缺血再灌注损伤中的表达和作用。方法 将20只小鼠随机分为对照组和肝缺血再灌注组,建立小鼠肝缺血再灌注模型。肝缺血再灌注组分别为缺血1 h再灌注6 h、再灌注12 h和再灌注24 h组。实时荧光定量PCR及Western Blot实验分别检测各组小鼠肝组织Sigma-1受体mRNA及蛋白表达水平。进一步研究Sigma-1受体在小鼠肝缺血再灌注损伤中的作用,将20只小鼠随机分为对照组、缺血再灌注组、Sigma-1受体激动剂组、Sigma-1受体激动剂加抑制剂组。建立小鼠肝缺血再灌注模型1 h前,向激动剂组小鼠腹腔注射Sigma-1受体激动剂4-苯基-1-(4-苯丁基)哌啶,激动剂加抑制剂组小鼠腹腔注射激动剂4-苯基-1-(4-苯丁基)哌啶和抑制剂NE-100。再灌注12 h后通过实时荧光定量PCR检测肝组织肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)、白介素(interleukin,IL)-6和IL-10 mRNA表达水平,ELISA法检测血清TNF-α、IL-6和IL-10水平,检测血清谷丙转氨酶(alanine aminotransferase,ALT)及谷草转氨酶(aspartate aminotransferase,AST),苏木精-尹红染色法观察肝组织病理学变化。结果 同对照组比较,缺血1 h再灌注12 h组Sigma-1受体表达水平明显升高(P<0.05)。同肝缺血再灌注组比较,Sigma-1受体激动剂组小鼠肝组织TNF-α和IL-6 mRNA表达水平下降,IL-10 mRNA表达水平升高,血清TNF-α、IL-6水平降低,IL-10水平升高,血清ALT、AST水平降低,肝组织病理学损伤减轻(P<0.05)。Sigma-1受体激动剂加抑制剂组小鼠肝组织TNF-α和IL-6 mRNA表达水平较Sigma-1受体激动剂组升高,IL-10 mRNA表达水平下降。血清TNF-α、IL-6水平升高,IL-10水平降低,血清ALT、AST水平升高,肝组织病理学损伤加重(P<0.05)。结论 在小鼠肝缺血再灌注后,Sigma-1受体表达水平升高,促进Sigma-1受体活化可减轻肝缺血再灌注损伤,其机制可能与抑制炎症反应有关。
英文摘要:
      Objective To investigate the expression and significance of Sigma-1 receptor in mice liver ischemia reperfusion injury. Methods Twenty mice were randomly divided into four groups: sham group, ischemia for 1 h followed by reperfusion for 6 h, 12 h and 24 h. The quantitative real-time PCR(qRT-PCR) and Western Blot were used to measure Sigma-1 receptor mRNA and protein expression levels in different groups. To explore the role of Sigma-1 receptor, twenty mice were randomly divided into four group: sham group, liver ischemia reperfusion group, Sigma-1 receptor agonist group, Sigma-1 receptor agonist and antagonist group. In the Sigma-1 receptor agonist group, mice were injected intraperitoneally with 1 mg/kg 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) prior to ischemia. In the Sigma-1 receptor agonist and antagonist group, the mice were pretreated with 1mg/kg NE-100 1 h before treatment with PPBP. The mRNA expression levels of tumor necrosis factor (TNF-α), interleukin (IL)-6 and IL-10 were detected by qRT-PCR. The serum inflammatory cytokines included TNF-α, IL-6 and IL-10 were detected by ELISA assay. The function of liver was evaluated by serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. The damage degree of liver tissues was determined by the histology analysis. Results Compared with sham group, the expression of Sigma-1 receptor were increased and peaked at 12 h. Compared with liver ischemia reperfusion group, the down-regulated TNF-α and IL-6 mRNA expre-ssion levels and up-regulated IL-10 mRNA expre-ssion levels were observed in Sigma-1 receptor agonist group. Pretreatment with PPBP reduced the serum TNF-α and IL-6 levels and increased IL-10 levels (P<0.05). Pretreatment with Sigma-1 receptor agonist improved liver function and ameliorated histopathological damage as compared to liver ischemia reperfusion group. Compared with Sigma-1 receptor agonist group, the upregulated TNF-α and IL-6 mRNA expression levels and down-regulated IL-10 mRNA expression levels were observed in Sigma-1 receptor agonist and antagonist group (P<0.05). Sigma-1 receptor agonist attenuated pathological changes of liver and decreased ALT and AST levels. Sigma-1 receptor agonist and antagonist aggravated the liver damage and increased ALT and AST levels as compare to Sigma-1 receptor agonist group. Conclusion The expression of Simga-1 receptor were upregulated in liver ischemia reperfusion. Activation of Sigma-1 receptor may alleviated liver ischemia reperfusion by suppressing inflammatory response.
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