Published online Mar 28, 2025. doi: 10.3748/wjg.v31.i12.103952
Revised: January 26, 2025
Accepted: March 3, 2025
Published online: March 28, 2025
Processing time: 111 Days and 16.2 Hours
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.
To identify molecular pathology contributing to hepatic injury during the progression of AOM-induced ALF.
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.
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.
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.