THE PATHWAYS OF CELL-DEATH - ONCOSIS, APOPTOSIS, AND NECROSIS

The pathways and identification of cell injury and cell death are of k ey importance to the practice of diagnostic and research toxicologic p athology. Following a lethal injury, cellular reactions are initially reversible. Currently, we recognize two patterns, oncosis and apoptosi s. Oncosis, derived from the Creek word ''swelling,'' is the common pa ttern of change in infarcts and in zonal killing following chemical to xicity, e.g., centrilobular hepatic necrosis after CCl4 toxicity. In t his common reaction, the earliest changes involve cytoplasmic blebbing , dilatation of the endoplasmic reticulum (ER), swelling of the cytoso l, normal or condensed mitochondria, and chromatin clumping in the nuc leus. In apoptosis, the early changes involve cell shrinkage, cytosoli c shrinkage, more marked chromatin clumping, cytoplasmic blebbing, swo llen ER on occasion, and mitochondria that are normal or condensed. Fo llowing cell death, both types undergo postmortem changes collectively termed ''necrosis.'' In the case of oncosis, this typically involves broad zones of cells while, in the case of apoptosis, the cells and/or the fragments are often phagocytized prior to their death by adjacent macrophages or parenchymal cells. In either case, the changes converg e to a pattern that involves mitochondrial swelling, mitochondrial flo cculent densities and/or calcification, karyolysis, and disruption of plasmalemmal continuity. The biochemical mechanisms of cell death are currently under intense study, particularly concerning the genes invol ved in the process. pro-death genes include p53, the ced-3/ICE proteas es, and the Pax family. Anti-death genes include ced-9/Bcl-2 and the a denovirus protein E1B. It is clear that ion deregulation, particularly that of [Ca2+](i) plays an important role in cell death following eit her apoptosis or oncosis. Genetic evidence strongly indicates that act ivation of proteases is an important step, possibly very near to the p oint where cell death occurs.