The Pathways of Cell Death: Oncosis, Apoptosis, and Necrosis

Abstract

The pathways and identification of cell injury and cell death are of key importance to the practice of diagnostic and research toxicologic pathology. Following a lethal injury, cellular reactions are initially reversible. Currently, we recognize two patterns, oncosis and apoptosis. Oncosis, derived from the Greek word "swelling," is the common pattern of change in infarcts and in zonal killing following chemical toxicity, e.g., centrilobular hepatic necrosis after CC14 toxicity. In this common reaction, the earliest changes involve cytoplasmic blebbing, dilatation of the endoplasmic reticulum (ER), swelling of the cytosol, normal or condensed mitochondria, and chromatin clumping in the nucleus. In apoptosis, the early changes involve cell shrinkage, cytosolic shrinkage, more marked chromatin clumping, cytoplasmic blebbing, swollen ER on occasion, and mitochondria that are normal or condensed. Following 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 converge to a pattern that involves mitochondrial swelling, mitochondrial flocculent 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 involved in the process. Pro-death genes include p53, the ced-3/ICE proteases, and the Bax family. Anti-death genes include ced-9/Bcl-2 and the adenovirus protein EIB. It is clear that ion deregulation, particularly that of [Ca2+]i plays an important role in cell death following either apoptosis or oncosis. Genetic evidence strongly indicates that activation of proteases is an important step, possibly very near to the point where cell death occurs.

Novel Mechanisms of Target Cell Death and Survival and of Therapeutic Action of IVIg in Pemphigus

“…Because oncosis is based on the loss of volume control related to a damage of the plasma membrane, the oncotic cells are visualized through the use of die exclusion tests. 38,39 The oncotic cell death is mediated by calpains, a family of Ca 2ϩ -activated neutral cysteine proteases. 41 Morphological changes in apoptosis include cell shrinkage, chromatin condensation (margination) rendering curved profile to the nucleus, ending in break of the nucleus (karyorhexis), normal or condensed mitochondria, and apoptotic body formation.…”

“…39 Both apoptosis and oncosis can lead to necrosis-the postmortem autolytic and degradative changes. 39 Necrosis is signaled by irreversible changes in the nucleus (karyolysis, pyknosis, and karyorhexis) and in the cytoplasm (condensation and intense eosinophilia, loss of structure, and fragmentation). Some of the detached keratinocytes that have drifted into the blister cavity in PV patients have intense eosinophilia.…”

“…For instance, TUNEL positivity is not specific for apoptosis, because either oncotic or apoptotic necrosis shows positive results with the TUNEL assay. 39 Likewise, evidence has been presented that questioned the validity of using DNA electrophoresis for identifying apoptosis. 56 It is not specific for apoptosis, because it occurs in lytic necrosis as well.…”

“…The lack of correlation of the acantholytic activities of PVIgG-1b and PVIgG-2b with their abilities to increase the number of TUNEL-and TBDpositive cells further suggested that the mechanisms of acantholysis induced by each individual PVIgG may not be identical. Because TUNEL staining is considered to be a specific marker of apoptosis, although it may also be positive in oncosis, and because TBD staining is more specific for oncosis, 38,39 we next sought to determine which of the two pathways of cell death are predominantly involved in mediating acantholysis caused by the PVIgGs under consideration. Effects of pemphigus and normal human IgG fractions on apoptosisrelated molecules in keratinocytes.…”

Role of the pro-survival molecule Bfl-1 in melanoma

“…Necrotic cells undergo morphological changes including cellular swelling (oncosis), disruption of organelle and plasma membranes and chromatin degradation, leading to the breakdown of organelles and resulting in the bursting of the cell 98,99 (Figure 1.4 Toll-like receptors and receptor for advanced glycation end products (RAGE) on macrophages and enhance the release of pro-inflammatory cytokines [100][101][102] .…”