Systemic histone release disrupts plasmalemma and contributes to necrosis in acute pancreatitis.

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.

• Authors: Peter Szatmary, Tingting Liu, Simon T Abrams, Svetlana Voronina, Li Wen, Michael Chvanov, Wei Huang, Guozheng Wang, David N Criddle, Alexey V Tepikin, Cheng-Hock Toh, Robert Sutton
• Journal: Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] (Pancreatology) 2017 Nov - Dec Vol. 17 Issue 6 Pg. 884-892 ISSN: 1424-3911 [Electronic] Switzerland
• PMID: 29102149 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 IAP and EPC. Published by Elsevier B.V. All rights reserved.

Chemical References

• Histones

Topics

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Animals
• Histones (blood, metabolism)
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Middle Aged
• Necrosis (metabolism)
• Pancreas (metabolism, pathology)
• Pancreatitis (blood, chemically induced, pathology)
• Young Adult