• Yan Geng, Qiang Ma, Ya-Nan Liu, Na Peng, Fang-Fang Yuan, Xing-Gui Li, Ming Li, Ying-Song Wu, Bing-ling Li, Wei-bing Song, Wei Zhu, Wei-Wen Xu, Jie Fan, and Lei Su.
• 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.
• J. Hepatol. 2015 Sep 1; 63 (3): 622-33.

Background & AimsLiver 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.MethodsTo 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.ResultsWe 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.ConclusionsThese 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.Copyright © 2015 European Association for the Study of the Liver. All rights reserved.

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