Peter Szatmary1, Tingting Liu2, Simon T Abrams3, Svetlana Voronina4, Li Wen5, Michael Chvanov4, Wei Huang6, Guozheng Wang3, David N Criddle4, Alexey V Tepikin4, Cheng-Hock Toh7, Robert Sutton5. 1. 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. 2. 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. 3. Institute of Infection and Global Health, University of Liverpool, Liverpool, L69 7BE, UK. 4. Department of Cellular and Molecular Physiology, University of Liverpool, Liverpool, L69 3BX, UK. 5. NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, University of Liverpool, Liverpool, L69 3GA, UK. 6. NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, University of Liverpool, Liverpool, L69 3GA, UK; Department of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre, West China Hospital, Sichuan University, Chengdu, 610041, China. 7. Institute of Infection and Global Health, University of Liverpool, Liverpool, L69 7BE, UK; Roald Dahl Haemostasis and Thrombosis Centre, Royal Liverpool University Hospital, Liverpool, L7 8XP, UK. Electronic address: toh@liverpool.ac.uk.
Abstract
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.
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 humanacute 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.
Authors: Christopher A Moxon; Yasir Alhamdi; Janet Storm; Julien M H Toh; Dagmara McGuinness; Joo Yeon Ko; George Murphy; Steven Lane; Terrie E Taylor; Karl B Seydel; Sam Kampondeni; Michael Potchen; James S O'Donnell; Niamh O'Regan; Guozheng Wang; Guillermo García-Cardeña; Malcolm Molyneux; Alister G Craig; Simon T Abrams; Cheng-Hock Toh Journal: Blood Adv Date: 2020-07-14