Mecanismos de lesión hepatocelular

Abstract

Cell death is a process accompanying many physiological and pathological situations in organisms. The first cell death pattern that was identified was cell necrosis, described by Virchow in 1871. It was subsequently seen that cell death was an integral part of normal cell and tissue differentiation mechanisms in superior organisms. In this respect early embryological studies revealed that cell death processes were required to model organisms in their final configuration. Morphogenesis systematically entails the removal and generation of new cell and tissue structures. A similar phenomenon is encountered during metamorphosis in invertebrates and inferior vertebrates, where massive tissue involution and cell clearance are coordinately developed physiological processes. This cell death process, designated apoptosis, was characterized by Kerr in 1965. Cell apoptosis and necrosis can be differentiated by a number of both morphological and biochemical parameters. Apoptosis is a controlled removal of the involved cell with no relevant changes in cell metabolism. This process is characterized by the sequential activation of a number of proteases known as caspases, which affect cysteine-aspartate bonds in the substrate. Caspase activation entails DNA fragmentation and cell architecture changes, associated with morphological changes such as nuclear DNA condensation, decreased cell volume, and the generation of apoptotic bodies with no intracellular contents release. Necrosis results from an extreme disruption of cell balance dramatically affecting cell metabolism with a drastic decrease in cell energy contents in the form of adenosine triphosphate (ATP), ion contents changes, increased mitochondrial and cell volume, and intracellular protease activation. This process ultimately leads to a disruption of cell membranes, and release of cell contents, which promotes a secondary inflammatory response. In the liver cell apoptosis usually has a focal distribution, whereas necrosis shows a regional distribution. Despite a clear-cut differentiation between apoptosis and necrosis, both types of cell death usually coexist in the liver, because one stimulus may induce apoptosis or necrosis depending on cell type involved, exposure extent, cell metabolic status, and the integrity of the machinery involved in cell death. In this sense a number of authors have suggested that apoptosis and necrosis are no separate processes but the opposing ends in only one cell mechanism designated necrapoptosis (1). Mitochondriagenerated ATP contents are a key factor in the regulation of apoptosis or necrosis induction during the process of cell death. In this respect a lesion involving a few mitochondria may be solved by autophagia of altered organelles. If more mitochondria are involved, and an adequate amount of proapoptotic factors is released while intracellular ATP levels remain, the cell undergoes apoptosis. If the cell undergoes a severe lesion, the dramatic reduction of ATP contents will not allow for many enerMechanisms of liver cell injury