Bhattarai SM, Jhawer A, Frampton G, Troyanovskaya E, DeMorrow S, McMillin M. Characterization of hepatic pathology during azoxymethane-induced acute liver failure. World J Gastroenterol 2025; 31(12): 103952 [DOI: 10.3748/wjg.v31.i12.103952]
Corresponding Author of This Article
Matthew McMillin, PhD, Assistant Professor, Huffington Department of Education, Baylor College of Medicine, 702 SW HK Dodgen Loop, Temple, TX 76548, United States. matthew.mcmillin@bcm.edu
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Gastroenterol. Mar 28, 2025; 31(12): 103952 Published online Mar 28, 2025. doi: 10.3748/wjg.v31.i12.103952
Characterization of hepatic pathology during azoxymethane-induced acute liver failure
Shadikchhya Maya Bhattarai, Ashwin Jhawer, Gabriel Frampton, Eleonora Troyanovskaya, Sharon DeMorrow, Matthew McMillin
Shadikchhya Maya Bhattarai, Ashwin Jhawer, Gabriel Frampton, Sharon DeMorrow, Matthew McMillin, Department of Internal Medicine, University of Texas at Austin Dell Medical School, Austin, TX 78701, United States
Eleonora Troyanovskaya, Sharon DeMorrow, Matthew McMillin, Department of Research, Central Texas Veterans Health Care System, Austin, TX 78701, United States
Sharon DeMorrow, Division of Pharmacology and Toxicology, University of Texas at Austin College of Pharmacy, Austin, TX 78701, United States
Matthew McMillin, Huffington Department of Education, Baylor College of Medicine, Temple, TX 76548, United States
Matthew McMillin, Department of Medicine, Baylor College of Medicine, Temple, TX 76548, United States
Co-first authors: Shadikchhya Maya Bhattarai and Ashwin Jhawer.
Author contributions: Bhattarai SM, Jhawer A, Frampton G, DeMorrow S and McMillin M performed experiments, analyzed data, and edited the manuscript; Bhattarai SM, Jhawer A and McMillin M wrote the manuscript; McMillin M designed and coordinated the study; All authors approved of the final version of the article.
Supported by The Department of Veterans Affairs Biomedical Laboratory Research & Development Service Award, No. BX003486 (to McMillin M); and National Institutes of Health Awards, No. R01DK112803 and No. R01DK135995 (to DeMorrow S).
Institutional animal care and use committee statement: Experiments were performed in compliance with the Animal Welfare Act and the Guide for the Care and Use of Laboratory Animals. Animal experiments were reviewed and approved by the University of Texas at Austin Institutional Animal Care and Use Committee, No. AUP-2021-00317.
Conflict-of-interest statement: All authors declare no competing interests.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was drafted according to the ARRIVE guidelines.
Data sharing statement: All experimental data are available upon request from the corresponding author at matthew.mcmillin@bcm.edu.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Matthew McMillin, PhD, Assistant Professor, Huffington Department of Education, Baylor College of Medicine, 702 SW HK Dodgen Loop, Temple, TX 76548, United States. matthew.mcmillin@bcm.edu
Received: December 5, 2024 Revised: January 26, 2025 Accepted: March 3, 2025 Published online: March 28, 2025 Processing time: 111 Days and 16.2 Hours
Abstract
BACKGROUND
Acute liver failure (ALF) is a loss of liver function due to a severe hepatic insult. Studies utilizing the azoxymethane (AOM) mouse model of ALF, which also generates hepatic encephalopathy, have primarily focused on development of neurological deficits. However, the molecular processes that generate liver damage have not been fully characterized. Therefore, a more comprehensive characterization of the hepatic consequences of AOM toxicity is needed to better understand this disease model.
AIM
To identify molecular pathology contributing to hepatic injury during the progression of AOM-induced ALF.
METHODS
C57BL/6 mice were injected with AOM to produce ALF and hepatic encephalopathy. Tissue was collected at defined stages of neurological decline up to coma. Liver injury, CYP2E1 expression, oxidative stress, inflammation, apoptosis, necroptosis, and hepatocellular senescence were assessed.
RESULTS
Increased hepatic necrosis and exacerbated liver injury were observed after AOM injection as mice progressed towards coma. CYP2E1 expression decreased in AOM-treated mice as liver injury progressed. Malondialdehyde, myeloperoxidase and other measures of oxidative stress were significantly increased during AOM-induced ALF. Hepatic CCL2 and tumor necrosis factor α expression increased as AOM-induced liver injury progressed. Mixed lineage kinase domain-like protein phosphorylation was increased early during the progression of AOM-induced liver injury. Measures of apoptosis and cellular senescence all increased as the time course of AOM progressed.
CONCLUSION
These data support that necrosis, oxidative stress, inflammation, apoptosis, and senescence were elevated in AOM-treated mice, with inflammation being the earliest significant change.
Core Tip: The azoxymethane (AOM) model of liver injury is used as a toxin-induced model to study acute liver failure and the development of hepatic encephalopathy (HE). After initial characterization of the liver injury in this model, little research has been performed to understand the specific cellular and molecular mechanisms of hepatic injury, with most studies focusing on neurological changes associated with HE. Here, we identify that the AOM model is associated with hepatic inflammation and oxidative stress that progresses to apoptosis, necrosis and hepatocellular senescence. These findings provide additional insight into this model and will help determine which components of hepatic pathology to investigate when therapeutic approaches are employed.
