Gut inflammation and adaptive immunity amplify acetaminophen toxicity in bowel and liver.

Autor: Alabbas SY; Mater Research, University of Queensland, Translational Research Institute, South Brisbane, Australia., Giri R; Mater Research, University of Queensland, Translational Research Institute, South Brisbane, Australia., Oancea I; Medical School, University of Queensland, Brisbane, Australia., Davies J; Mater Research, University of Queensland, Translational Research Institute, South Brisbane, Australia., Schreibner V; Mater Research, University of Queensland, Translational Research Institute, South Brisbane, Australia., Florin TH; Mater Research, University of Queensland, Translational Research Institute, South Brisbane, Australia., Begun J; Mater Research, University of Queensland, Translational Research Institute, South Brisbane, Australia.
Jazyk: angličtina
Zdroj: Journal of gastroenterology and hepatology [J Gastroenterol Hepatol] 2023 Apr; Vol. 38 (4), pp. 609-618. Date of Electronic Publication: 2023 Jan 16.
DOI: 10.1111/jgh.16102
Abstrakt: Background and Aim: Prevention of liver failure arising from accidental or deliberate paracetamol (acetaminophen [APAP]) overdose remains a vexed health problem despite well-publicized guidelines for its early detection and treatment. It is recognized that the gut may aggravate liver pathology, via the gut-liver axis. The main aim of this study was to assess the role of the colon in APAP-induced liver toxicity.
Methods: Liver necrosis and colitis were studied following sublethal doses of APAP administered intraperitoneally to C57Bl/6 wild-type (WT) mice, as well as to C57Bl/6 Winnie mice, which develop a spontaneous colitis caused by a SNP in Muc2, and WT mice with acute DSS-induced colitis. Repeated APAP exposure was studied in WT and Rag1 ko mice that lack mature T and B lymphocytes.
Results: APAP overdose resulted in significant colonic injury in WT mice (P < 0.05), which resolved by 24 h. Underlying colitis was not associated with liver necrosis, but colitis exacerbated APAP-induced liver injury and extended APAP-colonic injury. Prior APAP exposure exacerbated both APAP-liver and APAP-colonic injury more so in WT than Rag1 ko mice. APAP impaired barrier function with increased intestinal permeability and associated bacterial translocation to the liver and spleen in mice with the Winnie phenotype.
Conclusions: This study identifies novel roles for APAP in causing colitis, the amplification of APAP-liver toxicity where there is underlying colitis, and involvement of immune memory in APAP-toxicity. The latter could be key for decoding the poorly understood but important clinical entity of chronic APAP liver failure.
(© 2023 The Authors. Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)
Databáze: MEDLINE
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