The Potential Role of HMGB1 Release in Peritoneal Dialysis-Related Peritonitis
The Potential Role of HMGB1 Release in Peritoneal Dialysis-Related Peritonitis
复制标题
HMGB1 释放在腹膜透析相关性腹膜炎中的潜在作用
DOI：
10.1371/journal.pone.0054647
复制
发表时间：
2013-01-24
期刊：
影响因子：
3.7
通讯作者：
Mao, Haiping
中科院分区：
文献类型：
--
作者：
Cao, Shirong;Li, Shu;Mao, Haiping
高迁移率族蛋白1(HMGB1)是一种DNA结合核蛋白，在感染性疾病的发病机制中起着内源性危险信号的作用。然而，HMGB1在腹膜炎患者腹膜透析(PD)流出物中的潜在作用和来源尚不清楚。首先，为了评估腹膜透析液(PDE)中HMDB1的水平，本研究共纳入61例PD患者，其中42例有腹膜炎，19例无腹膜炎。记录人口学特征、症状、体检结果和实验室参数。用Western印迹和ELISA法测定PDE中HMGB1的水平。用双抗体夹心法测定肺泡灌洗液中肿瘤坏死因子-α和白介素6的浓度。通过动物模型，用甘草酸苷抑制HMGB1，观察HMGB1对内毒素诱导的小鼠腹膜炎的影响。体外培养的人腹膜间皮细胞系(HMRSV5)在脂多糖(LPS)刺激下，用Western印迹法或免疫荧光法分析细胞外HMGB1的含量和细胞内各组分的分布。结果表明，腹膜炎患者PDE中HMGB1水平明显高于正常对照组，且在抗生素有效治疗期间逐渐下降。此外，PDE患者血清HMGB1水平与白细胞计数、肿瘤坏死因子-α、IL-6水平呈正相关。然而，甘草酸预处理可减轻内毒素诱导的小鼠急性腹膜炎症和功能障碍。在培养的HMR SV5细胞中，内毒素可诱导HMGB1核浆移位和释放，并呈时间和剂量依赖关系。此外，胞内HMGB1定位于溶酶体中，并通过溶酶体介导的内毒素刺激后的分泌途径分泌。我们的研究表明，PD相关性腹膜炎时PDE中HMGB1水平升高，至少部分来自腹膜间皮细胞，这可能参与了PD相关性腹膜炎的发病过程，并在急性腹膜功能障碍中发挥关键作用。
High mobility group box 1 (HMGB1), a DNA-binding nuclear protein, has been implicated as an endogenous danger signal in the pathogenesis of infection diseases. However, the potential role and source of HMGB1 in the peritoneal dialysis (PD) effluence of patients with peritonitis are unknown. First, to evaluate HMDB1 levels in peritoneal dialysis effluence (PDE), a total of 61 PD patients were enrolled in this study, including 42 patients with peritonitis and 19 without peritonitis. Demographic characteristics, symptoms, physical examination findings and laboratory parameters were recorded. HMGB1 levels in PDE were determined by Western blot and ELISA. The concentrations of TNF-α and IL-6 in PDE were quantified by ELISA. By animal model, inhibition of HMGB1 with glycyrrhizin was performed to determine the effects of HMGB1 in LPS-induced mice peritonitis. In vitro, a human peritoneal mesothelial cell line (HMrSV5) was stimulated with lipopolysaccharide (LPS), HMGB1 extracellular content in the culture media and intracellular distribution in various cellular fractions were analyzed by Western blot or immunofluorescence. The results showed that the levels of HMGB1 in PDE were higher in patients with peritonitis than those in controls, and gradually declined during the period of effective antibiotic treatments. Furthermore, the levels of HMGB1 in PDE were positively correlated with white blood cells (WBCs) count, TNF-α and IL-6 levels. However, pretreatment with glycyrrhizin attenuated LPS-induced acute peritoneal inflammation and dysfunction in mice. In cultured HMrSV5 cells, LPS actively induced HMGB1 nuclear-cytoplasmic translocation and release in a time and dose-dependent fashion. Moreover, cytosolic HMGB1 was located in lysosomes and secreted via a lysosome-mediated secretory pathway following LPS stimulation. Our study demonstrates that elevated HMGB1 levels in PDE during PD-related peritonitis, at least partially, from peritoneal mesothelial cells, which may be involved in the process of PD-related peritonitis and play a critical role in acute peritoneal dysfunction.