系统性组蛋白释放破坏质膜，并导致急性胰腺炎发生坏死。
Systemic histone release disrupts plasmalemma and contributes to necrosis in acute pancreatitis.
机构信息
NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, University of Liverpool, Liverpool, L69 3GA, UK; Department of Cellular and Molecular Physiology, University of Liverpool, Liverpool, L69 3BX, UK.
NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, University of Liverpool, Liverpool, L69 3GA, UK; Institute of Infection and Global Health, University of Liverpool, Liverpool, L69 7BE, UK; Department of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre, West China Hospital, Sichuan University, Chengdu, 610041, China.
出版信息
Pancreatology. 2017 Nov-Dec;17(6):884-892. doi: 10.1016/j.pan.2017.10.002. Epub 2017 Oct 7.
BACKGROUND
Clinical and experimental acute pancreatitis feature histone release within the pancreas from innate immune cells and acinar cell necrosis. In this study, we aimed to detail the source of circulating histones and assess their role in the pathogenesis of acute pancreatitis.
METHODS
Circulating nucleosomes were measured in patient plasma, taken within 24 and 48 h of onset of acute pancreatitis and correlated with clinical outcomes. Using caerulein hyperstimulation, circulating histones were measured in portal, systemic venous and systemic arterial circulation in mice, and the effects of systemic administration of histones in this model were assessed. The sites of actions of circulating histones were assessed by administration of FITC-labelled histones. The effects of histones on isolated pancreatic acinar cells were further assessed by measuring acinar cell death and calcium permeability in vitro.
RESULTS
Cell-free histones were confirmed to be abundant in human acute pancreatitis and found to derive from pancreatitis-associated liver injury in a rodent model of the disease. Fluorescein isothianate-labelled histones administered systemically targeted the pancreas and exacerbated injury in experimental acute pancreatitis. Histones induce charge- and concentration-dependent plasmalemma leakage and necrosis in isolated pancreatic acinar cells, independent of extracellular calcium.
CONCLUSION
We conclude that histones released systemically in acute pancreatitis concentrate within the inflamed pancreas and exacerbate injury. Circulating histones may provide meaningful biomarkers and targets for therapy in clinical acute pancreatitis.
背景
临床和实验性急性胰腺炎的特征是固有免疫细胞和胰腺腺泡细胞坏死导致组织内组蛋白的释放。在这项研究中，我们旨在详细阐述循环组蛋白的来源，并评估其在急性胰腺炎发病机制中的作用。
方法
检测急性胰腺炎发病后 24 小时和 48 小时内患者血浆中循环核小体的含量，并与临床结果相关联。使用胆囊收缩素（caerulein）刺激建立小鼠模型，检测门静脉、体循环静脉和体循环动脉循环中的循环组蛋白，并评估该模型中系统性给予组蛋白的作用。通过给予 FITC 标记的组蛋白来评估循环组蛋白的作用部位。进一步通过测量体外分离的胰腺腺泡细胞的细胞死亡和钙通透性来评估组蛋白对胰腺腺泡细胞的作用。
结果
在人类急性胰腺炎中证实存在丰富的无细胞组蛋白，并在疾病的啮齿动物模型中发现其来源于与胰腺炎相关的肝损伤。系统性给予异硫氰酸荧光素标记的组蛋白可靶向胰腺，并在实验性急性胰腺炎中加重损伤。组蛋白诱导分离的胰腺腺泡细胞的质膜渗漏和坏死，其依赖于电荷和浓度，而不依赖于细胞外钙。
结论
我们得出结论，急性胰腺炎中系统性释放的组蛋白在炎症胰腺中浓缩，并加重损伤。循环组蛋白可能为临床急性胰腺炎的治疗提供有意义的生物标志物和治疗靶点。
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