World journal of gastroenterology · 2025
Characterization of hepatic pathology during azoxymethane-induced acute liver failure.
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Bhattarai Shadikchhya Maya, Jhawer Ashwin, Frampton Gabriel, Troyanovskaya Eleonora, DeMorrow Sharon, McMillin Matthew
Аннотация
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.
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.