Actinonin, a meprin A inhibitor, protects the renal microcirculation during sepsis.
Actinonin, a meprin A inhibitor, protects the renal microcirculation during sepsis.
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DOI：
10.1097/shk.0b013e3181ec39cc
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发表时间：
2011-02
期刊：
影响因子：
--
通讯作者：
Mayeux PR
中科院分区：
文献类型：
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作者：
Wang Z;Herzog C;Kaushal GP;Gokden N;Mayeux PR
脓毒症引起的急性肾损伤(AKI)发生在20%-50%的脓毒症患者中，几乎是脓毒症死亡率的两倍。由于败血症患者的治疗通常在症状出现后才开始，即使延迟也是有效的治疗将对患者的生存产生最大的影响。金属蛋白酶meprin A是一种由α-和β-亚基组成的寡聚复合体，在肾脏刷状缘膜上高度表达，能够降解包括细胞外基质蛋白和细胞因子在内的多种底物。本研究的目的是比较放线菌素的治疗潜力，它是一种meprin A的抑制剂，在脓毒症发生前后给予。在盲肠结扎穿孔(CLP)诱导脓毒症前30min或后7h分别给予放线宁治疗。活体视频显微镜用于显示肾小管周围毛细血管的血流和反应性氮的种类。在CLP前30min应用放线菌素可降低IL1-β水平，并在7h和18h阻止肾毛细血管灌注量的下降，即使在CLP后7h给药也能阻止肾毛细血管灌注量的下降。此外，即使在晚期使用放线菌素也能保持肾脏的形态，并降低血尿素氮和血肌酐浓度。这些数据表明，像放线素这样的药物应该被进一步评估为可能的治疗药物，因为同时针对脓毒症的早期全身和晚期器官损害效应应该具有最高的成功可能性。
Sepsis-induced acute renal injury (AKI) occurs in 20%–50% of septic patients and nearly doubles the mortality rate of sepsis. Since treatment in the septic patient is usually only begun after the onset of symptoms, therapy that is effective even when delayed would have the greatest impact on patient survival. The metalloproteinase meprin A, an oligomeric complex made of α- and β- subunits, is highly expressed at the brush-border membranes of the kidney and capable of degrading numerous substrates including extracellular matrix proteins and cytokines. The goal of the present study was to compare the therapeutic potential of actinonin, an inhibitor of meprin A when administered before and after the onset of sepsis. Mice were treated with actinonin at 30 min prior to or 7 h post induction of sepsis by cecal ligation and puncture (CLP). Intravital videomicroscopy was utilized to image renal peritubular capillary perfusion and reactive nitrogen species. Actinonin treatment 30 min before CLP reduced IL1-β levels and prevented the fall in renal capillary perfusion at 7 h and 18 h. Actinonin also prevented the fall in renal capillary perfusion even when administered at 7 h post CLP. In addition, even late administration of actinonin preserved renal morphology and lowered blood urea nitrogen and serum creatinine concentrations. These data suggest that agents like actinonin should be evaluated further as possible therapeutic agents because targeting both the early systemic and later organ-damaging effects of sepsis should have the highest likelihood of success.