Journal
JOURNAL OF HEPATOLOGY
Volume 66, Issue 4, Pages 836-848Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jhep.2016.11.017
Keywords
Acetaminophen; Hepatotoxicity; Sterile inflammation; Inflammasome; neutrophil; Monocyte; Toll-like receptor
Categories
Funding
- National Institutes of Health [DK070195, AA12916, DK102142]
- National Institute of General Medical Sciences [P20 GM103549, P30 GM118247]
- National Institute of Environmental Health Sciences, United States [T32 ES007079]
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Drug-induced acute liver failure carries a high morbidity and mortality rate. Acetaminophen overdose is the number one cause of acute liver failure and remains a major problem in Western medicine. Administration of N-acetyl cysteine is an effective antidote when given before the initial rise in toxicity; however, many patients present to the hospital after this stage occurs. As such, treatments which can alleviate late-stage acetaminophen-induced acute liver failure are imperative. While the initial mechanisms of toxicity are well described, a debate has recently occurred in the literature over whether there is a second phase of injury, mediated by inflammatory processes. Critical to this potential inflammatory process is the activation of caspase-1 and interleukin-1 beta by a molecular complex known as the inflammasome. Several different stimuli for the formation of multiple different inflammasome complexes have been identified. Formation of the NACHT, leucine-rich repeat (LRR) and pyrin (PYD) domains-containing protein 3 (Nalp3) inflammasome in particular, has directly been attributed to late-stage acetaminophen toxicity. In this review, we will discuss the mechanisms of acetaminophen-induced liver injury in mice and man with a particular focus on the role of inflammation and the inflammasome. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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