*Department of Academic Surgery and †Department of Radiology, Cork University Hospital and University College Cork, Cork, Ireland
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APOPTOSIS: PHYSIOLOGICAL CELL DEATHApoptosis, as a biological phenomenon, is readily identifiable by several characteristic features. It characteristically affects scattered single cells, not groups of contiguous cells as in necrosis, with the dying cell undergoing a relatively ordered form of cell death. This physiological cell death is characterized by cell shrinkage, cellular crenation, cytoplasmic and chromatin condensation, and internucleosomal DNA fragmentation (1). Changes in membrane glycosylation and lipid profiles, and alteration in expression of surface receptors have been observed. The apoptotic cells are rapidly phagocytosed and degraded by neighbouring cells or resident macrophages without an inflammatory response. This mechanism prevents the release of the phlogistic contents of cells and avoids the possibility of neighbouring host cell injury. The process differs significantly from cell death by necrosis or lysis where cells release their contents into the surrounding tissues and perpetuate the local inflammatory response. A glossary of terms pertinent to this review is included as an appendix.APOPTOSIS: MORPHOLOGICAL EVENTSDuring apoptosis, the dying cell undergoes a series of profound structural changes. The earliest event observed by electron microscopy is condensation of chromatin to form sharply circumscribed, uniformly dense, cresentic masses that abut the nuclear envelope (2). Nucleolar changes include the dispersal of peripheral nucleolar chromatin to form aggregates in the centre of the nucleus. Simultaneously with the nuclear changes, apoptotic cells detach from neighbouring cells, and specialized surface structures such as microvilli appear. Cell volume decreases, cell density increases, cytoplasmic organelles compact, and convolution of the cell and nuclear outline becomes evident (1) (Fig. 1). Cytoplasmic changes include cytoskeletal filament aggregation, clumping of ribosomal particles, and rearrangement of rough endoplasmic reticulum to form a series of concentric whorls (3). Cytoplasmic and nuclear condensation is followed by the production of numerous membrane protuberances at the plasma membrane that subsequently separate with sealing of the plasmalemma to form membrane-bound apoptotic bodies of varying sizes with condensed cytoplasm and crowded, intact cytoplasmic organelles. The production of apoptotic bodies is a late occurrence in the apoptotic process and is observed extensively in vitro, but less commonly in vivo. This observation emphasises the rapidity of the apoptotic process whereby apoptotic cells are rapidly phagocytosed in vivo prior to apoptotic body formation (4). Phagocytosis is mediated by adjacent epithelial cells, mononuclear phagocytes, or tumor cells. Once phagocytosed, apoptotic bodies are degraded by lysosomal enzymes derived from the ingesting cell. Rapid phagocytosis of apoptotic cells in vivo before their secondary degeneration helps explain the absence of inflammation associated with apoptosis. Apoptotic bodies that escape phagocytosis lose their integrity after an hour or so, resulting in swelling, loss of density, membrane rupture, and organelle disruption and dispersal referred to as secondary necrosis (Fig. 1).APOPTOSIS: BIOCHEMICAL EVENTSCytoskeletal and membrane alterationsCell shrinkage and apoptotic body formation require significant changes in both the cytoskeleton and plasma membrane lipid bilayer. Cytoskeletal changes include tissue transglutaminase activation, microtubule disruption, α-fodrin (non-erythroid spectrin) and actin cleavage, and a requirement for actin polymerization. These changes facilitate membrane budding and play a role in the maintenance of plasma membrane integrity in apoptotic cells (5). Membrane changes include redistribution of phosphatidylserine from its normal location on the inner leaf of the plasma membrane lipid bilayer to the outer leaf, exposure of surface sugar residues from loss of membrane sialic acid, and loss of expression of surface markers such as FcγRIII (CD16), complement regulatory molecules (CD45 and CD59), and adhesion molecules (CD11/CD18).