巴多昔芬甲基酯对大鼠肝脏缺血再灌注损伤的抗胆汁淤积作用

Anticholestatic Effect of Bardoxolone Methyl on Hepatic Ischemia-reperfusion Injury in Rats.

作者信息

Kim Joohyun, Hagen Catherine E, Kumar Suresh N, Park Jong-In, Zimmerman Michael A, Hong Johnny C

机构信息

Division of Transplant Surgery, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI.

Department of Pathology, Mayo Clinic, Rochester, MN.

出版信息

Transplant Direct. 2020 Jul 17;6(8):e584. doi: 10.1097/TXD.0000000000001017. eCollection 2020 Aug.

DOI:10.1097/TXD.0000000000001017

PMID:32766432

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7371100/

Abstract

BACKGROUND

Cholestasis is a sign of hepatic ischemia-reperfusion injury (IRI), which is caused by the dysfunction of hepatocyte membrane transporters (HMTs). As transcriptional regulation of HMTs during oxidative stress is mediated by nuclear factor erythroid 2-related factor 2, we hypothesized that bardoxolone methyl (BARD), a nuclear factor erythroid 2-related factor 2 activator, can mitigate cholestasis associated with hepatic IRI.

METHODS

BARD (2 mg/kg) or the vehicle was intravenously administered into rats immediately before sham surgery, 60 min of ischemia (IR60), or 90 min of ischemia (IR90); tissue and blood samples were collected after 24 h to determine the effect on key surrogate markers of bile metabolism and expression of HMT genes (Mrp (multidrug resistance-associated protein) 2, bile salt export pump, , sodium-taurocholate cotransporter, and organic anion-transporting polypeptide 1).

RESULTS

Significantly decreased serum bile acids were detected upon BARD administration in the IR60 group but not in the IR90 group. Hepatic tissue analyses revealed that BARD administration increased mRNA levels of and in the IR60 group, and it decreased those of bile salt export pump in the IR90 group. Protein levels of multidrug resistance-associated protein 2, multidrug resistance-associated protein 3, and sodium-taurocholate cotransporter were higher in the IR90 group relative to those in the sham or IR60 groups, wherein the difference was notable only when BARD was administered. Immunohistochemical and morphometric analyses showed that the area of expression for multidrug resistance-associated protein 2 and for sodium-taurocholate cotransporter was larger in the viable tissues than in the necrotic area, and the area for multidrug resistance-associated protein 3 was smaller; these differences were notable upon BARD administration.

CONCLUSIONS

BARD may have the potential to change HMT regulation to mitigate cholestasis in hepatic IRI.

摘要

背景

胆汁淤积是肝缺血再灌注损伤（IRI）的一个标志，其由肝细胞膜转运体（HMTs）功能障碍引起。由于氧化应激期间HMTs的转录调控由核因子红细胞2相关因子2介导，我们推测巴多昔芬甲基（BARD），一种核因子红细胞2相关因子2激活剂，可减轻与肝IRI相关的胆汁淤积。

方法

在假手术、60分钟缺血（IR60）或90分钟缺血（IR90）前立即给大鼠静脉注射BARD（2mg/kg）或赋形剂；24小时后采集组织和血液样本，以确定对胆汁代谢关键替代标志物和HMT基因（多药耐药相关蛋白（Mrp）2、胆盐输出泵、牛磺胆酸钠共转运体和有机阴离子转运多肽1）表达的影响。

结果

在IR60组中，给予BARD后检测到血清胆汁酸显著降低，但在IR90组中未降低。肝组织分析显示，给予BARD可使IR60组中Mrp2和有机阴离子转运多肽1的mRNA水平升高，而在IR90组中可降低胆盐输出泵的mRNA水平。与假手术组或IR60组相比，IR90组中多药耐药相关蛋白2、多药耐药相关蛋白3和牛磺胆酸钠共转运体的蛋白水平更高，其中仅在给予BARD时差异显著。免疫组织化学和形态计量学分析表明，多药耐药相关蛋白2和牛磺胆酸钠共转运体在存活组织中的表达面积大于坏死区域，而多药耐药相关蛋白3的表达面积较小；给予BARD后这些差异显著。