title: Acetaminophen hepatotoxicity and repair: the role of sterile inflammation and innate immunity.
abstract: Acetaminophen (APAP) hepatotoxicity because of overdose is the most frequent cause of acute liver failure in the western world. Metabolic activation of APAP and protein adduct formation, mitochondrial dysfunction, oxidant stress, peroxynitrite formation and nuclear DNA fragmentation are critical intracellular events in hepatocytes. However, the early cell necrosis causes the release of a number of mediators such as high-mobility group box 1 protein, DNA fragments, heat shock proteins (HSPs) and others (collectively named damage-associated molecular patterns), which can be recognized by toll-like receptors on macrophages, and leads to their activation with cytokine and chemokine formation. Although pro-inflammatory mediators recruit inflammatory cells (neutrophils, monocytes) into the liver, neither the infiltrating cells nor the activated resident macrophages cause any direct cytotoxicity. In contrast, pro- and anti-inflammatory cytokines and chemokines can directly promote intracellular injury mechanisms by inducing nitric oxide synthase or inhibit cell death mechanisms by the expression of acute-phase proteins (HSPs, heme oxygenase-1) and promote hepatocyte proliferation. In addition, the newly recruited macrophages (M2) and potentially neutrophils are involved in the removal of necrotic cell debris in preparation for tissue repair and resolution of the inflammatory response. Thus, as discussed in detail in this review, the preponderance of experimental evidence suggests that the extensive sterile inflammatory response during APAP hepatotoxicity is predominantly beneficial by limiting the formation and the impact of pro-inflammatory mediators and by promoting tissue repair.
authors: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA. hjaeschke@kumc.edu
authors: Hartmut
authors: H
authors: Jaeschke
authors: C David
authors: CD
authors: Williams
authors: Anup
authors: A
authors: Ramachandran
authors: Mary L
authors: ML
authors: Bajt
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D015551:Autoimmunity / Q000276:immunology; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology / Q000473:pathology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007113:Immunity, Innate; D058847:Inflammasomes / Q000276:immunology; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D008115:Liver Regeneration / Q000276:immunology*; D009336:Necrosis / Q000139:chemically induced
chemical_list: D058847:Inflammasomes; D018836:Inflammation Mediators; D000082:Acetaminophen