Circulating Histone Levels Reflect Disease Severity in Animal Models of Acute Pancreatitis

Objectives Extracellular histones are rapidly cleared by the liver and rarely detectable in the circulation unless there is extensive cell death, as in severe trauma and sepsis. This study investigated whether circulating histones are elevated in experimental acute pancreatitis models and correlate to disease severity. Methods Acute pancreatitis was induced in mice by: (1) 4 or (2) 12 intraperitoneal injections of cerulein (50 g/kg) at 1 hour apart; (3) retrograde infusion of 3.5% sodium taurocholate into the biliopancreatic duct. Mice were sacrificed at various time points to collect blood and tissues. Severity of pancreatitis was assessed by biochemical markers and histopathology. Circulating histones were determined by Western blotting. Results Four cerulein injections induced edematous pancreatitis, whereas 12 cerulein injections and ductal taurocholate infusion caused necrotizing pancreatitis. Circulating histones were barely detectable in the blood of animals with edematous pancreatitis but significantly increased in necrotizing pancreatitis. The levels of circulating histones were strongly correlated to histopathological scores of necrosis of the pancreas. Conclusions Circulating histones increased significantly in necrotizing pancreatitis due to extensive pancreatic acinar cell death. Levels of circulating histones may have translational potential as a biomarker of disease severity.