Changes in the Gene Expression Associated with Carbon Tetrachloride-Induced Liver Fibrosis Persist after Cessation of Dosing in Mice

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Abstract
Recent studies have shown that gene expression profiles change in the livers of animals treated acutely with toxic chemicals such as carbon tetrachloride (CCl4). This study was undertaken to evaluate the changes in gene expression in mouse liver immediately after a long-term treatment with CCl4 and possible effects of treatment cessation on these changes. Adult 129/SvpcJ mice were treated twice a week with CCl4 at 1 ml/kg in olive oil for 4 weeks. Hepatic pathological changes observed in the CCl4-treated mice included necrosis, inflammation, and fibrosis, along with increased serum alanine aminotransferase activities. Consistent with these changes, expression of genes involved in cell death, cell proliferation, metabolism, DNA damage, and fibrogenesis were upregulated as detected by microarray analysis and confirmed by real-time RT-PCR. Four weeks after CCl4 treatment cessation, the pathological changes were recovered, with the exception of fibrosis, which was not completely reversed. Most of the gene expression profiles also returned to the control level; however, the fibrogenetic genes remained at a high level of expression. These results demonstrate that changes in gene expression profile correlate with pathological alterations in the liver in response to CCl4 intoxication. Most of these changes are recoverable upon withdrawal of the toxic insult. However, liver fibrosis is a prolonged change both in gene expression and histopathological alterations.

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