Mechanisms and pathophysiological significance of sterile inflammation during acetaminophen hepatotoxicity.

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 addition, many cytokines and chemokines modulate tissue injury by affecting the intracellular signaling events of cell death rather than toxicity of leukocytes. Reasons for the controversial results in this area are also discussed.

• Authors: Hartmut Jaeschke, Anup Ramachandran
• Journal: Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association (Food Chem Toxicol) Vol. 138 Pg. 111240 (Apr 2020) ISSN: 1873-6351 [Electronic] England
• PMID: 32145352 (Publication Type: Journal Article, Review)
• Copyright: Copyright © 2020 Elsevier Ltd. All rights reserved.

Chemical References

• Chemokines
• Cytokines
• Acetaminophen

Topics

• Acetaminophen (toxicity)
• Animals
• Chemical and Drug Induced Liver Injury (immunology, physiopathology)
• Chemokines (metabolism)
• Cytokines (metabolism)
• DNA Fragmentation (drug effects)
• Hepatocytes (drug effects, metabolism)
• Humans
• Immunity, Innate
• Inflammation (chemically induced, immunology, metabolism, physiopathology)
• Killer Cells, Natural (drug effects, immunology)
• Liver (drug effects, immunology, physiopathology)
• Macrophages (drug effects, immunology)
• Mice
• Monocytes (drug effects, immunology)
• Necrosis (chemically induced)
• Neutrophils (drug effects, immunology)