Mechanisms of liver cell injury.

Liver cell death is triggered by a number of insults arising from the external environment or from within the cell. These insults may engage cell surface receptors with death domaines leading to a proteolytic cascade involving initiator and executioner caspases and an apoptotic demise. Alternatively, the insults may profoundly disrupt mitochondrial function and result in loss of homeostasis accompanied by activation of hydrolases and a necrotic or lytic demise. The distinction between apoptotic and necrotic cell death has become blurred recently by the recognition that the same stimuli can induce either form of cell death as well as caspase independent apoptosis. Mitochondria play a key role in the shape of cell death; selective release of mediators amplifies the apoptosis program and profound loss of mitochondrial function leads to necrosis. Reactive oxygen metabolites and nitric oxide participate as initiating factors and modulators. The extensive knowledge gained in recent years about the mechanisms of cell death will undoubtedly lead to new and exciting advances in the prevention and treatment of liver diseases. Important targets include death receptors, death signaling mechanisms, the mitochondrial permeability transition and approaches which selectively inhibit or activate cell death in parenchymal versus nonparenchymal cells.