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J Hepatol. 2015 Sep;63(3):622-33. doi: 10.1016/j.jhep.2015.04.010. Epub 2015 Apr 27.

Heatstroke induces liver injury via IL-1β and HMGB1-induced pyroptosis.

Author information

1
Department of Gastroenterology, 303 Hospital of People's Liberation Army, Nanning 530021, PR China; Department of Intensive Care Unit, General Hospital of Guangzhou Military Command, Guangzhou 510010, PR China. Electronic address: gytools@sina.com.
2
State Key Laboratory of Organ Failure Research, Institute of Antibody Engineering, Southern Medical University, Guangzhou 510515, PR China. Electronic address: mqqqm2006@163.com.
3
Department of Graduate School, Southern Medical University, Guangzhou 510515, PR China.
4
Department of Graduate School, Southern Medical University, Guangzhou 510515, PR China; Department of Intensive Care Unit, General Hospital of Guangzhou Military Command, Guangzhou 510010, PR China.
5
Department of Graduate School, Southern Medical University, Guangzhou 510515, PR China; Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
6
Department of Neurology, The Fifth People's Hospital of Chongqing, Chongqing 400062, PR China; Department of Intensive Care Unit, General Hospital of Guangzhou Military Command, Guangzhou 510010, PR China.
7
State Key Laboratory of Organ Failure Research, Institute of Antibody Engineering, Southern Medical University, Guangzhou 510515, PR China.
8
Department of Intensive Care Unit, General Hospital of Guangzhou Military Command, Guangzhou 510010, PR China.
9
Department of Toxicology, Guangzhou Center for Disease Control and Prevention, Guangzhou 510515, PR China.
10
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. Electronic address: jif7@pitt.edu.
11
Department of Intensive Care Unit, General Hospital of Guangzhou Military Command, Guangzhou 510010, PR China. Electronic address: drggyn@163.com.

Abstract

BACKGROUND & AIMS:

Liver injury is a common complication of heat stroke (HS), and often constitutes a direct cause for patient death. The cellular and molecular mechanism underlying HS-induced liver injury remains unclear. Recent evidence indicates that inflammasome plays an important role in mediating sterile inflammation triggered by tissue damage. Using a rat HS model, we identified a novel mechanism by which inflammasome-dependent interleukin-1β (IL-1β) activation and hepatocyte pyroptosis mediate HS-induced liver injury.

METHODS:

To induce HS, rats were subjected to heat exposure. Inhibition of inflammasomes was achieved by RNA silencing and pharmacologic inhibitor prior to heat exposure. Inflammasome assembly, caspase-1 activation, histological changes, as well as serum levels of liver enzymes were measured.

RESULTS:

We demonstrated that the onset of HS activated inflammasome in the liver as evidenced by increased capase-1 activity and the association of inflammasome components NOD-like receptor family pyrin domain containing 3 (Nlrp3) and apoptosis speck-like protein containing a caspase-recruitment domain (ASC); and the activated inflammasome, in turn, induced IL-1β activation and hepatocyte pyroptosis, and subsequent augmented liver injury. HS-induced hepatocyte inflammasome activation seems to be high-mobility group box 1 (HMGB1) dependent. Inhibition of Nlrp3, caspase-1, or HMGB1 prevented HS-induced liver inflammation and ameliorated liver injury.

CONCLUSIONS:

These findings demonstrate an important role of HMGB1 in mediating inflammasome activation in the development of liver injury following HS, and suggest that targeting inflammasome may represent a novel therapeutic strategy to limit cell death and prevent liver failure after HS.

KEYWORDS:

Caspase-1; Hyperthermia; Inflammasome; Nlrp3

PMID:
25931416
DOI:
10.1016/j.jhep.2015.04.010
[Indexed for MEDLINE]

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