title: Role of the inflammasome in acetaminophen-induced liver injury and acute liver failure.
abstract: 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-1β 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.
authors.affiliation: Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Woolbright
authors.affiliation: Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Jaeschke
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000276:immunology* / Q000473:pathology; D006801:Humans; D058847:Inflammasomes / Q000187:drug effects* / Q000276:immunology*; D017114:Liver Failure, Acute / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018448:Models, Immunological
chemical_list: D058847:Inflammasomes; D000082:Acetaminophen
keywords: Acetaminophen; Hepatotoxicity; Inflammasome, neutrophil; Monocyte; Sterile inflammation; Toll-like receptor