Characterization of Hepatic Injury During the Azoxymethane Model of Acute Liver Failure

医学 氧化应激 内科学 硫代乙酰胺 谷胱甘肽 肝损伤 肝性脑病 胃肠病学 神经炎症 胆汁淤积 病理 炎症 内分泌学 生物 肝硬化 生物化学
作者
Matthew McMillin,Ashwin Jhawer,Gabriel Frampton,Shadikchhya M. Bhattarai,Eleonora Troyanovskaya
出处
期刊:The FASEB Journal [Wiley]
卷期号:36 (S1)
标识
DOI:10.1096/fasebj.2022.36.s1.r3952
摘要

Acute liver failure (ALF) results from a significant loss of liver function and has few effective treatments and poor clinical outcomes. ALF is associated with neurological dysfunction, called type A hepatic encephalopathy (HE), which greatly increases mortality. One of the commonly used models of type A HE is the azoxymethane (AOM) mouse model, which is associated with hepatocyte necrosis, neuroinflammation and oxidative stress. That being said, there have been no extensive analyses into the hepatic pathology associated with AOM-induced liver injury. Therefore, the aim of this study was to characterize the hepatic injury during the AOM model of type A HE.C57Bl/6 mice were administered 100 mg/kg of AOM and were euthanized at various stages of neurological decline and tissue was collected. These stages include normal (vehicle-treated), prior to neurological decline (pre), minor neurological decline (minor), significant neurological decline (major), and coma. Liver injury was assessed by measuring serum ALT and AST levels as well as liver H&E staining. Serum albumin, bile acids, glutathione (GSH) and ammonia were measured to determine liver function. Various aspects of oxidative stress, inflammation and cell death were assessed by measuring CYP2E1, Nrf2, SOD1, CCL2, IL-1β, IL-6, LC3-II, phosphorylated MLKL, cleaved caspase 3, p21 and TGFβ1 expression using real-time PCR, immunoblotting, ELISA or immunohistochemistry. All data were analyzed using GraphPad Prism software with results presented as mean +/- SEM. Differences between two groups were compared using the Student's t-test and differences between three groups were determined using ANOVA.AOM-treated mice had significant elevations of serum ALT and AST and hepatic necrosis as neurological decline progressed. CYP2E1 expression decreased throughout the stages of neurological decline, with the greatest suppression in mice at coma. Measures of oxidative stress and signaling had the largest increase when mice were at major neurological decline, which was also associated with the largest increase of inflammatory chemokines and cytokines. Measures of necroptosis, apoptosis and cellular senescence were also dysregulated, with coma mice showing the highest degrees of cell death and increased cellular senescence.These data demonstrate that AOM-treated mice have increased oxidative stress and inflammation resulting from the metabolic dysregulation from AOM toxicity. This leads to cell death through multiple different mechanisms and an impairment of regeneration due to increased cellular senescence.

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