Apoptosis in hepatic pathophysiology.

Apoptosis is a fundamental biologic process that is important in many physiologic and pathophysiologic processes in the liver. Although dysregulation of apoptosis may contribute to a wide range of diseases, the role of this process in liver disease and pathophysiology has only recently begun to be recognized and remains to be fully defined. Several important questions remain unanswered: How does excessive apoptosis in response to injury contribute to inflammation and fibrogenesis in the liver? How does control of apoptosis contribute to the regulation of hepatic structure following injury? What is the role of death receptors in hepatic disease? Can an understanding of apoptosis be helpful in therapeutic modulation of specific liver diseases or liver cancer? The identification of target molecules involved in apoptosis raises the prospect of pharmacologic modulation that may result in better treatment options for patients with liver diseases. Inhibition of apoptosis is likely to be useful in treating fulminant hepatic failure or in organ preservation before transplantation. In these situations, treatment is for a limited period, and the potential hazards of nonselective long-term inhibition of apoptosis are minimized. Safe and organ-specific inhibitors of apoptosis would be required for prolonged treatment of chronic liver diseases. For treatment of liver tumors, the goal is to induce apoptosis selectively in cancer cells. Drugs that decrease the apoptotic threshold by modulating the intracellular regulatory mechanisms and drugs that enhance the susceptibility of cancer cells to undergo immune-mediated apoptosis will be useful in the treatment of liver cancers. The rapid advances in the understanding of the intracellular mechanisms and the regulation of apoptosis will ultimately result in a better understanding of the role of apoptosis in the pathophysiology of liver diseases and may allow therapeutic modulation of this process.