Suppression of PTRF alleviates the polymicrobial sepsis induced by cecal ligation and puncture in mice.
Suppression of PTRF alleviates the polymicrobial sepsis induced by cecal ligation and puncture in mice.
复制标题
抑制 PTRF 可减轻小鼠盲肠结扎和穿刺引起的多种微生物败血症。
DOI：
10.1093/infdis/jit364
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Jin,Yang
中科院分区：
文献类型：
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作者：
Zheng,Yijie;Lee,Seonjin;Liang,Xiaoliang;Wei,Shuquan;Moon,Hyung-Geun;Jin,Yang
背景：脓毒症和脓毒症相关的器官衰竭是毁灭性的疾病。了解详细的细胞/分子机制参与脓毒症应导致识别新的治疗targets.Methods。盲肠结扎和穿刺（CLP）被用来作为一个多微生物脓毒症模型在体内，以确定死亡率和终末器官损伤。采用巨噬细胞作为体外细胞模型进行机制研究。结果。PTRF+/-小鼠在CLP后存活时间更长，器官损伤更少。在PTRF+/−小鼠的血浆、巨噬细胞和重要器官中观察到一氧化氮（NO）和iNOS生物合成减少。使用CLP后的急性脓毒症模型，我们发现iNOS−/−小鼠的存活率与PTRF+/−小鼠相当。类似地，聚合酶I转录释放因子（PTRF）缺陷导致体外巨噬细胞中iNOS和NO/ROS产生减少。脂多糖（LPS）增强了PTRF和TLR 4在脂筏中的共定位和相互作用。PTRF的缺失阻断了LPS后TLR 4/Myd 88复合物的形成。与此一致的是，PTRF的缺乏损害了TLR 4信号传导，如通过减少p-JNK，p-ERK，和p-p38所示，这些都是参与iNOS转录的上游因子。
Background.Sepsis and sepsis-associated organ failure are devastating conditions. Understanding the detailed cellular/molecular mechanisms involved in sepsis should lead to the identification of novel therapeutic targets.Methods.Cecal ligation and puncture (CLP) was used as a polymicrobial sepsis model in vivo to determine mortality and end-organ damage. Macrophages were adopted as the cellular model in vitro for mechanistic studies.Results.PTRF+/− mice survived longer and suffered less organ damage after CLP. Reductions in nitric oxide (NO) and iNOS biosynthesis were observed in plasma, macrophages, and vital organs in the PTRF+/− mice. Using an acute sepsis model after CLP, we found that iNOS−/− mice had a comparable level of survival as the PTRF+/− mice. Similarly, polymerase I transcript release factor (PTRF) deficiency resulted in decreased iNOS and NO/ROS production in macrophages in vitro. Mechanistically, lipopolysaccharide (LPS) enhanced the co-localization and interaction between PTRF and TLR4 in lipid rafts. Deletion of PTRF blocked formation of the TLR4/Myd88 complex after LPS. Consistent with this, lack of PTRF impaired the TLR4 signaling, as shown by the decreased p-JNK, p-ERK, and p-p38, which are upstream factors involved in iNOS transcription.Conclusion.PTRF is a crucial regulator of TLR4 signaling in the development of sepsis.