Apoptosis: a mechanism of acute and chronic liver injury
Authors: M E Guicciardi
Journal: Gut (2005)

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. 1-4Paradoxically, 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.[9][10] 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. 11-14We will also review some pro-and antiapoptotic therapies currently in use (or in clinical trial) or potentially useful for the treatment of human diseases, including liver diseases. DEFINITION OF APOPTOSIS cApoptosis is a highly organised and genetically controlled type of cell death, essential during embryonic development to ensure proper organogenesis 15 as well as for the health of adult organisms.It is characterised by a number of distinct morphological alterations, such as chromatin condensation and marginalisation, cell shrinkage, and plasma membrane blebbing, which are accompanied by biochemical features such as DNA fragmentation, membrane alterations (that is, exposure of phosphatidylserine on the outside of the plasma membrane), and degradation of specific cellular proteins, as a result of the massive activation of a large number of intracellular proteases and endonucleases.In the latest stages, the dying cell is fragmented into membrane bound vesicles containing relatively intact organelles and chromatin residues named ''apoptotic bodies'' 16 which are readily engulfed by neighbouring cells and professional phagocytes, such as resident macrophages or, in the liver, by Kupffer cells (fig 1).Supposedly, the efficient clearance of dead cells prevents triggering of the immune response that may follow spontaneous lysis of the apoptotic bodies and release of proinflammatory cytokines, making it ideal for remodelling of the tissue.Perhaps the most remarkable feature of apoptosis is its highly regulated nature.Apoptosis occurs through activation of a cell death machinery via specific molecular pathways that are under the tight control of a complex network of proteins and their endogenous inhibitors.This allows the cell to control its fate by starting the apoptotic programme and relieving the apoptotic inhibitions, whenever is necessary, or preventing the engagement of the death machinery under normal conditions.The control occurs mainly at checkpoints in the pathways that can also potentially be used as targets for therapeutic modulation of apoptosis.Many of the above concepts are however likely not relevant to ''apoptosis'' in pathobiology.Whereas physiological apoptosis is tightly restricted to discrete subsets of cells, both spatially and temporally, pathological apoptosis involves large numbers of cells, is non-selective, can be sustained over time, and often occurs in an inflammatory milieu.Therefore, the concept of 1024