Apoptosis: a mechanism of acute and chronic liver injury.

Correspondence to: Dr G J Gores, Mayo Clinic College of Medicine, 200 First St SW, Rochester, Minnesota 55905, USA; gores.gregory@ mayo.edu _________________________ P rompt removal of unwanted cells, such as senescent, damaged, genetically mutated, or virus infected cells, is crucial for the maintenance of liver health. This process is naturally achieved through a highly regulated programmed form of cell death called apoptosis. In healthy organisms, the number of cells eliminated by apoptosis equals the number of cells generated by mitosis, ensuring the proper organ homeostasis. In addition, ‘‘physiological’’ apoptosis allows the removal of cells with virtually no release of proinflammatory cytokines and minimal immune response. However, in pathophysiological situations, the balance between cell proliferation and cell death is often altered, with the consequent loss of tissue homeostasis and the onset of several liver diseases. Insufficient apoptosis, with failure of removal of cells carrying mutated genes, and unregulated proliferation within the context of a persistent inflammatory milieu, can promote the development of liver and biliary cancer. Paradoxically, a chronic apoptotic stimulus can also predispose to cancer development due to the high rate of regeneration invoked in the tissue, which elevates the risk of mitotic errors. In contrast, excessive and/or sustained apoptosis can lead to acute injuries, such as fulminant hepatitis and reperfusion damage, 6 or even chronic sustained injuries, such as alcoholic liver disease, cholestatic liver disease, and viral hepatitis. Therefore, therapeutic strategies to inhibit apoptosis in liver injury, or selectively kill malignant cells in tumours, have the potential to provide a powerful tool for the treatment of liver disease. Indeed, with an improved understanding of the molecular pathways and the pathophysiological role of apoptosis, new drugs aimed at therapeutically modulating apoptosis are now available for clinical trials and/or as new therapeutic options for the treatment of several human diseases. In this review, we will focus on the role of apoptosis in selected liver diseases, such as alcoholic liver disease, viral hepatitis, cholestatic liver diseases, non-alcoholic liver disease, and hepatocellular carcinoma. We will also review some proand antiapoptotic therapies currently in use (or in clinical trial) or potentially useful for the treatment of human diseases, including liver diseases.