Unfractionated heparin attenuates histone-mediated cytotoxicity in vitro and prevents intestinal microcirculatory dysfunction in histone-infused rats

作者：Chengrui Zhu, Yingjian Liang, Xu Li, Ning Chen, Xiaochun Ma · 发表于：The Journal of Trauma: Injury, Infection, and Critical Care · 年份：2019 · DOI：10.1097/ta.0000000000002387 · 被引用次数：44 · 研究领域：Neutrophil, Myeloperoxidase and Oxidative Mechanisms、Proteoglycans and glycosaminoglycans research、Cell Adhesion Molecules Research

BACKGROUND: Extracellular histones are major mediators of organ dysfunction and death in sepsis, and they may cause microcirculatory dysfunction. Heparins have beneficial effects in sepsis and have been reported to bind to histones and neutralize their cytotoxicity. The aim of this study was to investigate the impact of histones on intestinal microcirculation and the intestinal endothelium and to discuss the protective effect of unfractionated heparin (UFH) on the endothelial cytotoxicity and microcirculatory dysfunction induced by histones. METHODS: Anesthetized rats were infused with 30 mg/kg calf thymus histones, and UFH was administered intravenously at a concentration of 100 IU/kg per hour. The intestinal microcirculation was visualized and measured with incident dark field microscope. Plasma von Willebrand factor (vWF) and soluble thrombomodulin were detected, and structural changes in the rat intestinal microvascular endothelium were examined. The effects of histones and UFH on cell survival rates, vWF release and calcium influx were investigated in human intestinal microvascular endothelial cells (HIMECs). RESULTS: Histone infusion caused severe intestinal microcirculatory dysfunction in the absence of obvious hemodynamic changes, and UFH protected intestinal microcirculation in histone-infused rats. Concentrations of the plasma endothelial injury markers vWF and soluble thrombomodulin were elevated, and structural abnormalities were found in the intestinal microvascu...