Role of extracellular histones in the cardiomyopathy of sepsis
Role of extracellular histones in the cardiomyopathy of sepsis
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DOI：
10.1096/fj.14-268730
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发表时间：
2015-05-01
期刊：
影响因子：
4.8
通讯作者：
Ward, Peter A.
中科院分区：
文献类型：
--
作者：
Kalbitz, Miriam;Grailer, Jamison J.;Ward, Peter A.
本研究的目的是确定多微生物脓毒症（成年雄性C57BL/6小鼠）心功能障碍与血浆细胞外组蛋白的出现之间的关系。手术包括通过盲肠结扎和穿刺诱导败血症，并使用超声心动图/多普勒参数测量心功能。我们评估了组蛋白在心肌细胞（CMs）（小鼠和大鼠）中引起氧化还原状态和细胞内[Ca2+](i)水平失衡的能力。我们还研究了组蛋白干扰灌注了组蛋白的心脏的功能和电反应的能力。主要研究结果显示，脓毒症血浆中出现的细胞外组蛋白需要C5a受体、多形核白细胞（PMNs）和含Nacht、LRR和pyd结构域的蛋白3 （NLRP3）炎性体。体外暴露于组蛋白会导致氧化还原系统和[Ca2+]稳态的丧失(i)，以及线粒体功能的缺陷。灌注组蛋白的心脏引起电和功能障碍。最后，在脓毒症小鼠体内中和组蛋白可显著降低心功能障碍参数。多微生物脓毒症时，组蛋白引起心脏功能障碍。这些事件可以通过组蛋白中和来减轻，这表明组蛋白可能是脓毒症中减少心功能障碍的靶点。
The purpose of this study was to define the relationship in polymicrobial sepsis (in adult male C57BL/6 mice) between heart dysfunction and the appearance in plasma of extracellular histones. Procedures included induction of sepsis by cecal ligation and puncture and measurement of heart function using echocardiogram/Doppler parameters. We assessed the ability of histones to cause disequilibrium in the redox status and intracellular [Ca2+](i) levels in cardiomyocytes (CMs) (from mice and rats). We also studied the ability of histones to disturb both functional and electrical responses of hearts perfused with histones. Main findings revealed that extracellular histones appearing in septic plasma required C5a receptors, polymorphonuclear leukocytes (PMNs), and the Nacht-, LRR-, and PYD-domains-containing protein 3 (NLRP3) inflammasome. In vitro exposure of CMs to histones caused loss of homeostasis of the redox system and in [Ca2+](i), as well as defects in mitochondrial function. Perfusion of hearts with histones caused electrical and functional dysfunction. Finally, in vivo neutralization of histones in septic mice markedly reduced the parameters of heart dysfunction. Histones caused dysfunction in hearts during polymicrobial sepsis. These events could be attenuated by histone neutralization, suggesting that histones may be targets in the setting of sepsis to reduce cardiac dysfunction.