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• W2593108503 abstract "<b><i>Background:</i></b> The mechanism by which bile acids induce liver injury in cholestasis remains controversial.<b> </b>Although high levels of bile acids are toxic when applied to liver cells, the level of toxic bile acids in the liver of most cholestatic animals and patients is <10 μ<smlcap>M</smlcap>, indicating there must be alternative mechanisms. Recent studies suggest that the inflammatory response may play an important role in bile acid-induced liver injury, as pro-inflammatory cytokine expression is stimulated by bile acids in mouse hepatocyte cultures. To elucidate the mechanisms of bile acid-induced liver injury, we assessed signs of liver damage and gene expression in <i>Abcb4</i>^<i>-/-</i> mice, a well-known model for cholestasis. <b><i>Key Messages:</i></b> Elevated plasma levels of bile acids were detected as early as 10 days after birth and at all later ages in <i>Abcb4</i>^<i>-/-</i> mice compared to their wild-type littermate controls. Parallel increases in expression of Tnfα, Ccl2, Cxcl1, and Cxcl2 mRNA occurred at these early time points and throughout 12 weeks in <i>Abcb4</i>^<i>-/-</i> livers. Marked hepatic neutrophil infiltration was first detected in 3-week mice, whereas histological evidence of liver injury was not detected until 6-weeks of age. Subsequent in vitro studies demonstrated that normal hepatocytes but not other non-parenchymal liver cells responded to bile acids with inflammatory cytokine induction. <b><i>Conclusion:</i></b> Bile acids induce the expression of pro-inflammatory cytokines in hepatocytes in <i>Abcb4</i>^<i>-/-</i> mice that initiates an inflammatory response. This inflammatory response plays an important role in the development of cholestatic liver injury in this and other cholestatic conditions. Furthermore, understanding of these inflammatory mechanisms should lead to new therapeutic approaches for cholestatic liver diseases." @default.
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• W2593108503 date "2017-01-01" @default.
• W2593108503 modified "2023-10-17" @default.
• W2593108503 title "The Role of Inflammation in the Mechanisms of Bile Acid-Induced Liver Damage" @default.
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• W2593108503 doi "https://doi.org/10.1159/000450916" @default.
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