Mechanisms and pathophysiological significance of sterile inflammation during acetaminophen hepatotoxicity.

Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association
Hartmut Jaeschke, Anup Ramachandran

Abstract

Acetaminophen (APAP) is a widely used analgesic drug, which can cause severe liver injury after an overdose. The intracellular signaling mechanisms of APAP-induced cell death such as reactive metabolite formation, mitochondrial dysfunction and nuclear DNA fragmentation have been extensively studied. Hepatocyte necrosis releases damage-associated molecular patterns (DAMPs) which activate cytokine and chemokine formation in macrophages. These signals activate and recruit neutrophils, monocytes and other leukocytes into the liver. While this sterile inflammatory response removes necrotic cell debris and promotes tissue repair, the capability of leukocytes to also cause tissue injury makes this a controversial topic. This review summarizes the literature on the role of various DAMPs, cytokines and chemokines, and the pathophysiological function of Kupffer cells, neutrophils, monocytes and monocyte-derived macrophages, and NK and NKT cells during APAP hepatotoxicity. Careful evaluation of results and experimental designs of studies dealing with the inflammatory response after APAP toxicity provide very limited evidence for aggravation of liver injury but support of the hypothesis that these leukocytes promote tissue repair. In addit...Continue Reading

Citations

Aug 31, 2020·Expert Opinion on Drug Metabolism & Toxicology·Jephte Y AkakpoHartmut Jaeschke
Aug 23, 2020·International Journal of Molecular Sciences·Linda FeldbrüggeMoritz Schmelzle
Aug 5, 2020·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Hartmut Jaeschke, Anup Ramachandran
Jan 24, 2021·Journal of Biochemical and Molecular Toxicology·Hartmut Jaeschke, Anup Ramachandran
Dec 29, 2020·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Jian ZouJian-Bo Wan
Dec 24, 2020·International Journal of Molecular Sciences·Layla ShojaieLily Dara
Nov 27, 2020·Expert Review of Gastroenterology & Hepatology·David S Umbaugh, Hartmut Jaeschke
Apr 16, 2021·Medicinal Research Reviews·Yusha Luo, Tingting Zhou
Apr 30, 2021·Frontiers in Cell and Developmental Biology·Shanshan WeiWenqun Li
May 5, 2021·Cell Proliferation·Huiting GuoMin Zheng
Jun 15, 2021·Frontiers in Physiology·Tao ChenPeng Chen
Sep 22, 2021·Toxicological Sciences : an Official Journal of the Society of Toxicology·Samikshya PoudelUdayan Apte

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