Yan Geng1, Qiang Ma2, Ya-Nan Liu3, Na Peng4, Fang-Fang Yuan5, Xing-Gui Li6, Ming Li7, Ying-Song Wu7, Bing-ling Li8, Wei-bing Song8, Wei Zhu9, Wei-Wen Xu7, Jie Fan10, Lei Su11. 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.
BACKGROUND & AIMS:Liver injury is a common complication of heat stroke (HS), and often constitutes a direct cause for patientdeath. 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.
Authors: Brian C Davis; Holly Tillman; Raymond T Chung; Richard T Stravitz; Rajender Reddy; Robert J Fontana; Brendan McGuire; Timothy Davern; William M Lee Journal: Liver Int Date: 2017-02-17 Impact factor: 5.828
Authors: Jessica S Lin; Duha Zaffar; Haris Muhammad; Peng-Sheng Ting; Tinsay Woreta; Amy Kim; Ruhail Kohli; Kiyoko Oshima; Andrew Cameron; Benjamin Philosophe; Shane Ottmann; Russell Wesson; Ahmet Gurakar Journal: ACG Case Rep J Date: 2022-07-12