Mechanisms and prevention of hepatocyte cell death

In many liver diseases, hepatocyte damage occurs upon exposure to toxic bile acids, inflammatory cytokines and increased levels of reactive oxygen species (ROS). Detailed information of the signaling pathways involved in hepatocyte damage will facilitate the discovery of new targets for intervention. Therefore, in this thesis the modulation of signaling pathways involved in three models of hepatocyte cell death was studied: 1) glycochenodeoxycholic acid (GCDCA), as a model for acute bile acid toxicity, 2) the cytokine tumor necrosis factor (TNF) a in combination with the transcriptional inhibitor actinomycin D (ActD, to inhibit nuclear factor-KB (NF-KB) activation), as a model for acute liver failure and 3) the superoxide anion donor menadione as a model for oxidative stress-induced apoptosis. These models are clinically relevant, because bile acids, cytokines and reactive oxygen species are present at increased levels in most liver diseases. In addition to a detailed investigation of the mechanisms of cell death in these models, the effects of potential drugs for the treatment of liver diseases were studied