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Role of the inflammasome in acetaminophen-induced liver injury and acute liver failure

  • Benjamin L. Woolbright
    Affiliations
    Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA
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  • Hartmut Jaeschke
    Correspondence
    Corresponding author. Address: Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, KS 66160, USA. Tel.: +1 913 588 7969; fax: +1 913 588 7501.
    Affiliations
    Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA
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Published:November 29, 2016DOI:https://doi.org/10.1016/j.jhep.2016.11.017

      Summary

      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.

      Keywords

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