Apoptosis: Programmed Cell Death

BASIC SCIENCE FOR SURGEONS Apoptosis: Programmed Cell Death

Nai-Kang Kuan BS; Edward Passaro, Jr, MD

urrently there is much interest and excitement in the understanding of how cells undergo the process of apoptosis or programmed cell death. Understanding how, why, and when cells are instructed to die may provide insight into the aging process, autoimmune syndromes, degenerative diseases, and malignant transformation. This re- viewC focuses on the development of apoptosis and describes the process of programmed cell death, some of the factors that incite or prevent its occurrence, and finally some of the diseases in which it may play a role. The hope is that in the not too distant future we may be able to modify or thwart the apoptotic process for therapeutic benefit.

The notion that cells are eliminated or ab- tact with that target cell. In experiments, the sorbed in an orderly manner is not new. death or survival of neurons could be modu- What is new is the recognition that this is lated by the loss of NGF, by antibodies, or an important physiologic process.1 More by the addition of exogenous NGF. During than 40 years ago embryologists noted that development and maturation, many types during morphogenesis cells and tissues ofneuronsarebeingproducedinexcess.This were being deleted in a predictable fash- seemingly extravagant waste of excessive ion. During human development as on- neurons has several survival advantages for togeny recapitulates phylogeny, there is the theorganism.Forexampleneuronsthathave loss of branchial arches, the tail, the cloaca, found their way to the wrong target cell do and webbing between fingers. Pediatric not survive. In turn, the large excess of neu- surgery is replete with examples where rons make it unlikely that any target cell will there has been failure of this process, with not make contact with the appropriate neu- double aortic arch, sacrococcygeal tera- ron. The result is that an excellent balance tomas, extrophy of the bladder, and syn- is achieved between the surviving neurons dactyly to name but a few. It is now rec- and target cells. ognized that apoptosis continues on after development, while the organism is un- APOPTOSIS VS NECROSIS dergoing growth and maturation. In fact the process is life long. Apoptosis stands in sharp contrast to Anexcellentexampleoftheimportance necrosis—a condition familiar to surgeons of programmed cell death during both de- (Figure). Necrosis is caused by an exter- velopment and maturation is provided by nal noxious stimulus and involves con- the vertebrate nervous system. Here again tiguous portions of tissue. The process is therewaslong-standingrecognitionthatdur- passive and pathologic in that injury is pro- ing development the death of neurons is a duced. The insult causes lysis or rupture regular feature, but only recently has the ex- of cell membranes and the leakage of cyto- tent of the neuronal death (50%) and its im- sol into the surroundings. Organelles such portance become understood.2 The seminal as mitochondria are easily injured whereas observations include the discovery of a nerve the nucleus, protected by a strong mem- growth factor (NGF) produced by the tar- brane, may remain intact. The escape of the get cell that is required for the sustenance cytosol releases kinins into the tissue that of the neuron responsible for making con- incite inflammation. Edema, capillary di- lation, and macrophage aggregation ensue. From the Department of Toxicology, University of Cincinnati, Cincinnati, Ohio The inflammatory response takes hours to (Mr Kuan); and the Department of Surgery, West Los Angeles Veterans Affairs days to both occur and subside and leaves Medical Center (Dr Passaro), Los Angeles, Calif. traces of its presence by scar formation.

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 Apoptosis (literally a “falling off” Necrosis Apoptosis as with leaves) occurs because of a preprogrammed process contained within the cell that can be either activated by the cell itself or by external stimuli. Specific genes have been Chromatin identified that regulate the process. It Chromatin is an active and physiologic process Segments that requires the cell to expend energy in causing its own demise. Ini- tially, an individual cell becomes loose Nucleus or detached from its neighbors and Mitochondria Cytochrome morphologically shrinks. The cell Bcl-2 c membrane becomes contorted and White Blood Cell folded into blebs. Intracellular pro-

teases (interleukin converting en- Necrosis Apoptosis zymes) activate enzymes that begin to 3 Process Pathological Physiologic cleave the cytoskeletal framework. Energy Passive Active The chromatin becomes condensed Stimulus External Internal near the nuclear membrane and is cut Host response Inflammation None into regular repeating lengths. The Cell membrane Ruptured Intact Blebs 36+9 blebs of the intact cell membrane, Mitochondria Loss Intact (Release Cytochrome c) Duration Days Hours many of which now contain con- Result Scar None/apoptotic bodies densed nuclear fragments (apoptotic bodies), pinch off as separate Differences between apoptosis and necrosis. packets. Although these packets may undergo phagocytosis by macro- For example, in both the developing mous cells on the surface. Similarly, phages, there is no inflammatory re- and mature intestine the survival of during menstruation the sloughed sponse. The process is relatively rapid, an individual cell can be dependent uterineliningquicklyundergoesapop- reaching completion in approxi- on contact with an extracellular ma- tosis as the cells are deprived of hor- mately 2 hours. Apoptotic bodies are trix, or a threshold level of a growth mones necessary for survival. Above the only visible remains. For these rea- or a stimulatory substance.5 The loss all, maintaining the appropriate cell sons the process and its magnitude of either can cause the activation of mass of an organ depends on a balance went undetected for a long time. the cell’s intrinsic destruction or sui- between production of new cells and cide mechanism. During the devel- the loss of old cells by programmed APOPTOSIS AND opment of the gut, the solid tube of cell death. HOMEOSTASIS cells develops a lumen by apoptosis of the centrally located cells because MECHANISM OF APOPTOSIS Activation of apoptosis is only partly of a loss of contact with the periph- understood and the object of much eral extracellular matrix. In the fully Two opposing mechanisms that investigation. The process may be ini- developed bowel, as enterocytes mi- maintain homeostatic control of tiated by agents such as bacterial tox- grate toward the tip of the villus they apoptosis are the Fas ligand8 and the ins, viral infections, and cytolytic T lose contact with the basement mem- protein expressed by the Bcl-2 gene.9 lymphocytes.4 This pathway can be brane and become apoptotic.6 Hence The Fas ligand promotes cell death thought of as serving a “housekeep- the bowel does not slough off viable by binding to Fas, a cell membrane ing function” to ensure that cells that cells into its lumen, but rather cells receptor, initiating a series of intra- have become injured, infected, al- that are dead. This is similar to the cellular events leading to apopto- tered or incompetent are removed in skin that sloughs off dead cells at its sis. Fas expression can be induced an expeditious and efficient man- surface. The death of cells that have by encountering an antigen, as oc- ner. For example, a lymphocyte in- lost contact with the extracellular ma- curs with T cells, or it may be ex- fected with the Epstein-Barr virus, a trix or with each other is termed pressed at some low level by the tis- virus with a potential to cause malig- anoias (“homelessness”). Similarly, sue itself. The Fas ligand can be nant transformation of the cell, would neurons that fail to receive sufficient induced and up-regulated by the be stimulated to undergo apoptosis NGF, for whatever reason, undergo presence of kinins such as interleu- and thereby lessen the risk to the or- apoptosis.7 kins. The complexing of Fas to the ganism. The virus or other noxious Programmed cell death is impor- Fas ligand, whether on the surface agents activate specific receptors and tant in many physiologic processes. of the same cell or with another cell, genes for apoptosis resulting in The most evident example is the skin. initiates the apoptotic process. prompt elimination of the affected Epidermal cells grow from the basal The Bcl-2 gene is an interesting lymphocytes. germinal layer and migrate to the sur- and important gene involved in hu- The other major pathway can be face. En route they undergo apopto- man malignancies such as B-cell lym- conceived as a homeostatic process. sis, resulting in flattened dead squa- phomas from which it derives its

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 name. It has been highly conserved them. The result is the loss of most these cancer therapies rely on induc- from primitive worms up to humans of the secreting thyroid. This is not ingapoptosisincellsthathavesuffered and, therefore, thought to be impor- the result of attacking monocytes DNA damage.18 Similarly tumors with tant. It is the best characterized gene and macrophages, but rather of ex- p53 deficiencies are much less respon- of a family of genes that may affect cessive activation of programmed sive to anticancer therapies. programmed cell death. Protein ex- cell death. This is an important pressed by Bcl-2 inhibits the apop- modification of our paradigm of totic process and is powerful enough some autoimmune diseases such as Corresponding author: Edward Pas- to block the process in the early Hashimoto thyroiditis. saro, Jr, MD, Department of Surgery, phases.10 Bcl-2 is intimately associ- However, other chronic auto- West Los Angeles Veterans Affairs ated with the outer mitochondrial immune diseases such as systemic lu- Medical Center, 11301 Wilshire Blvd, membrane. Bcl-2 inhibits early apop- pus erythematosus appear to result Los Angeles, CA 90073. totic events by preventing the re- from the unbridled attack of reactive lease of cytochrome c from the mito- lymphocytes on otherwise healthy tis- chondrial membrane into the sue.14 Both in experimental animals REFERENCES cytosolic space.11 If cytochrome is re- and in patients with this disease, it can leased into the mitochondria, it will be shown that the reactive lympho- 1. 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