Circulating histones are major mediators of systemic inflammation and cellular injury in patients with acute liver failure.
Acute liver failure (ALF) is a life-threatening systemic disorder. Here we investigated the impact of circulating histones, recently identified inflammatory mediators, on systemic inflammation and liver injury in murine models and patients with ALF. We analyzed histone levels in blood samples from 62 patients with ALF, 60 patients with chronic liver disease, and 30 healthy volunteers. We incubated patients' sera with human L02 hepatocytes and monocytic U937 cells to assess cellular damage and cytokine production. d-galactosamine plus lipopolysaccharide (GalN/LPS), concanavalin A (ConA), and acetaminophen (APAP) were given to C57BL/6N mice to induce liver injury, respectively, and the pathogenic role of circulating histones was studied. Besides, the protective effect of nonanticoagulant heparin, which can bind histones, was evaluated with in vivo and ex vivo investigations. We observed that circulating histones were significantly increased in patients with ALF, and correlated with disease severity and mortality. Significant systemic inflammation was also pronounced in ALF patients, which were associated with histone levels. ALF patients' sera induced significant L02 cell death and stimulated U937 cells to produce cytokines, which were abrogated by nonanticoagulant heparin. Furthermore, circulating histones were all released remarkably in GalN/LPS, ConA, and APAP-treated mice, and associated with high levels of inflammatory cytokines. Heparin reduced systemic inflammation and liver damage in mice, suggesting that it could interfere with histone-associated liver injury. Collectively, these findings demonstrate that circulating histones are critical mediators of systemic inflammation and cellular damage in ALF, which may be potentially translatable for clinical use.
Department of Anesthesiology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.
Zongmei
Z
Wen
Medical Research Center, Beijing Chao-Yang hospital, Capital Medical University, Beijing 100020, China.
Zhen
Z
Lei
Department of Forth Cadre, Chinese PLA Army General Hospital, Beijing 100700, China.
Lu
L
Yao
Department of Anesthesiology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.
Ping
P
Jiang
Department of Oncology, First Hospital of Qinhuangdao, Qinhuangdao 066000, China.
Tao
T
Gu
Beijing Youan Hospital, Capital Medical University, Beijing 100069, China.
Feng
F
Ren
Beijing Youan Hospital, Capital Medical University, Beijing 100069, China.
Yan
Y
Liu
Beijing Youan Hospital, Capital Medical University, Beijing 100069, China.
Chunyan
C
Gou
Beijing Youan Hospital, Capital Medical University, Beijing 100069, China.
Xiuhui
X
Li
Medical Research Center, Beijing Chao-Yang hospital, Capital Medical University, Beijing 100020, China.
Tao
T
Wen
D000328:Adult; D000368:Aged; D000818:Animals; D016022:Case-Control Studies; D016207:Cytokines / Q000378:metabolism; D003710:Demography; D005260:Female; D006493:Heparin / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology*; D006657:Histones / Q000097:blood*; D006801:Humans; D007249:Inflammation / Q000097:blood* / Q000150:complications*; D018836:Inflammation Mediators / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000473:pathology; D017114:Liver Failure, Acute / Q000097:blood* / Q000150:complications* / Q000401:mortality; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D012720:Severity of Illness Index
D016207:Cytokines; D006657:Histones; D018836:Inflammation Mediators; D006493:Heparin
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