Apoptotic cell death as a target for the treatment of acute and chronic liver injury

Acute liver failure can develop as a consequence of viral hepatitis, drug- or toxin-induced toxicity or rejection after liver transplantation, whereas chronic liver injury can be due to long-term exposure to alcohol, chemicals, chronic viral hepatitis, metabolic or cholestatic disorders. During acute and chronic liver injury, liver cells are exposed to increased levels of cytokines, oxidative stress and bile acids. This may result in cell damage followed by necrotic and apoptotic cell death of hepatocytes and proliferation of stellate cells. Eventually, this may lead to loss of liver function. Effective therapies for acute and chronic liver diseases are not available. Hepatocytes, the parenchymal cells of the liver, are well equipped with protective mechanisms to prevent cell death. As long as these protective pathways can be activated, the balance will be in favour of cell survival. However, the balance between cell survival and cell death is delicate and can be easily tipped towards cell death during liver injury. Therefore, insight into the cellular mechanisms leading to cell death is of relevance to understand liver diseases. This can result in identification of novel intervention targets in order to prevent cell death. The aim of this thesis is to investigate apoptotic mechanisms in acute and chronic liver injury in order to develop strategies to protect hepatocytes against apoptotic cell damage. In contrast to the loss of hepatocytes, chronic liver injury is associated with the proliferation and activation of hepatic stellate cells. These cells play a pivotal role in liver fibrosis. Thus, contrary to the prevention of cell death in hepatocytes, induction of apoptosis in activated stellate cells may constitute a relevant therapeutic strategy during chronic liver diseases. An important anti-apoptotic mechanism is the activation of the transcription factor NF-κB which results in the activation of anti-apoptotic genes. This thesis describes the role of NF-κB in the protection against apoptosis in hepatocytes during acute liver injury (chapter 3 in vitro and chapter 4 in vivo) and chronic liver injury (chapter 5). Furthermore, NF-κB-regulated Inhibitor of Apoptosis Protein2 (cIAP2) is highlighted as a new target of therapy. In chronic cholestatic liver diseases, the accumulation of bile acids in the liver is thought to play a role in causing hepatocyte damage. This thesis describes the extent of apoptotic cell death in hepatocytes in an experimental model of extrahepatic cholestasis and the ability of these cells to adapt to bile acid-induced apoptosis (chapter 5). Patients with cholestatic liver disease are often treated with ursodeoxycholic acid (UDCA), but its protective mechanism of action is not well defined yet. Chapter 6 of this thesis describes the possible mechanisms behind the anti-apoptotic action of taurine-conjugated UDCA. Liver injury eventually results in excessive deposition of extracellular matrix referred to as fibrogenesis. In this process, the activation and proliferation of stellate cells (fibroblasts-like cells) is a key event. Therefore, the stellate cell is an attractive target for anti-fibrotic therapies. One promising approach is the induction of apoptotic cell death in activated stellate cells. However, it is crucial that this induction should be selectively aimed at stellate cells while leaving hepatocytes unaffected. Therefore, a gene delivery tool which selectively targets to activated stellate cells is developed and tested (chapter 7). This will allow cell selective gene modulation in this important cell type during chronic liver diseases accompanied by fibrosis. This thesis describes some of the mechanisms leading to apoptotic cell death during liver disease and provides tools to selectively interfere with this process.