Circulating Histone Levels Reflect Disease Severity in Animal Models of Acute Pancreatitis.
OBJECTIVE
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 μg/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.
From the *The Medical School of Southeast University, Nanjing, China; †Institute of Infection and Global Health, University of Liverpool; ‡NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, Liverpool, UK; §Department of Intensive Care Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
Xilong
X
Ou
Zhenxing
Z
Cheng
Tingting
T
Liu
Zhongming
Z
Tang
Wei
W
Huang
Peter
P
Szatmary
Shuyun
S
Zheng
Robert
R
Sutton
Cheng Hock
CH
Toh
Nan
N
Zhang
Guozheng
G
Wang
D000208:Acute Disease; D000704:Analysis of Variance; D000818:Animals; D015415:Biomarkers / Q000097:blood; D015153:Blotting, Western; D002108:Ceruletide; D004195:Disease Models, Animal; D006657:Histones / Q000097:blood*; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D010195:Pancreatitis / Q000097:blood* / Q000139:chemically induced / Q000473:pathology; D019283:Pancreatitis, Acute Necrotizing / Q000097:blood* / Q000139:chemically induced / Q000473:pathology; D012720:Severity of Illness Index; D013656:Taurocholic Acid
D015415:Biomarkers; D006657:Histones; D013656:Taurocholic Acid; D002108:Ceruletide