This is one of the most exciting areas of research in pathology and medicine. It was first recognized by pathologists in 1972, named after the Greek word for "falling off". It is a distinctive mode of cell death that shares some similarities with other recognized types of cell death, such as coagulative necrosis. It permeates almost every stage of development and its regulation and control have been directly linked with carcinogenesis. The following information has been adopted from Robbins Pathologic Basis of Disease, 6th Edition, 1999.
Developmental Stage Actions Programmed destruction of cells during embryogenesis Implantation of egg, organogenesis, developmental involution, metamorphosis Hormone-dependent involution in the adult Menstrual cycle, atrophy of ovaries during menopause, regression of lactating breast after weaning, atrophy of prostate following castration Cell deletion in proliferating cell populations Intestinal crypt epithelium Cell death in tumors Tumor regression and in active tumor cell growth Acute inflammatory response Death of neutrophils Death of immune cells Cytokine depletion leads to death of T and B lymphocytes Cell death induced by cytotoxic T cells Cellular immune rejection, graft versus host disease Organ atrophy following duct obstruction Pancreas, partoid gland, kidney Some viral diseases Viral hepatitis in the liver forming Councilman bodies Cell death produced by injurious stimuli
Heat, radiation, cytotoxic anticancer drugs, and hypoxia
The changes that occur in the cell are best observed ultrastructurally, that is, under the electron microscope. The most important changes are cell shrinkage, chromatin condensation, formation of cytoplasmic blebs and apoptotic bodies, and phagocytosis of apoptotic cells or bodies. A critical distinction, contrasting with necrosis, is the lack of inflammation. These morphologic (structural) changes are accompanied by biochemical changes as well. There is cleavage of specialized proteins known as caspases (a class of cysteine proteases). Protein cross linking reduces the cell cytoplasm into a shrunken remnant (apoptotic bodies). The DNA breaks down in a characteristic fashion yielding large pieces composed of 50-300 kilobases. These are further broken down as cellular enzymes known as endonucleases cleave the DNA into multiples of 180-200 bases. Finally, alterations of the cellular plasma membrane permit early recognition of these cells by macrophages, without the usual recruitment of inflammatory cells.
Apoptosis is associated with numerous disease states. The following are the most well-researched examples.
Increased Apoptosis-Excessive Cell Death Decreased Apoptosis-Increased Cell Survival Spinal muscular atrophies (neurodegnerative disorders) Cancers esp. those with p53 mutations and hormone dependent (breast, prostate, ovary) Ischemic injury (myocardial infarction) Autoimmune disorders Virus induced lymphocyte depletion (AIDS)
These complicated and sequential changes are orchestrated by a series of molecular events that are still being discovered. As of this writing, the following pathways have been elucidated.
Signaling Pathways (Tumor Necrosis Factor, Fas-Fas ligand, p53)
Transmembrane and intracellular signals may initiate or end the process. Transmembrane signals include binding to receptors for growth factors, cytokines, and hormones. Binding of receptors of the tumor necrosis factor (TNF) and Fas-Fas ligand are two of the most important examples. Apoptosis initiated by intracellular signals include binding of glucocorticoids to nuclear receptors, physical agents such as heat, radiation, and hypoxia, and viral infections.
T cells have a Fas receptor which binds to a Fas ligand, produced by cells of the immune system. When the binding occurs, apoptosis is initiated through caspase 8, eliminating activated lymphocytes, reducing and limiting the host response.
TNF-receptor mediated signaling may lead to either apoptosis or survival. In both scenarios, TNF binds to the cellular receptor leading to a cytoplasmic association of the TNFR-adapter protein with a death domain (TRADD). If TRADD binds to Fas-Fas death domain (FADD), it leads to caspase activation and apoptosis. However, in some situations, TRADD may bind to other adapter proteins leading to inactivation of transcription nuclear factor-kappaB (NF-kB). This is performed by stimulating degradation of its inhibitor protein IkB. This balance between NF-kB/IkB is important in determining whether a cell undergoes apoptosis or survival.
In some tumors, there is constitutive activation of NK-kB promoting survival. In some diseases, such as spinal muscle atrophy, there are mutations in some inhibitors of apoptosis such as neuronal apoptosis inhibitory protein (NAIP) which suppresses TNF-induced cell death, promoting survival. The selective mutations lead to spinal cord motor neuron loss.
DNA damage from agents such as radiation or chemotherapy leads to cellular accumulation of p53. This protein arrests the cell cycle allowing the cell time to carry out repair. If repair fails, p53 will trigger apoptosis. Some cancers have a mutated or absent p53 which will favor cell survival.
Control and Integration Stage (Bcl-2, Apaf-1, cytochrome c)
Bcl-2 is one of the key enzymes of apoptosis, normally suppressing or inhibiting the process. It shares a similarity to genes in the worm Caenorhabditis elegans which have been termed ced genes, or C. elegans death genes. These genes control the growth and development of the worm. Bcl-2, the mammalian counterpart of the ced-9 gene, is located in the outer mitochondrial membrane, endoplasmic reticulum, and nuclear envelope. It suppresses apoptosis by decreasing permeability in the mitochondrial membrane. It may also bind and sequester proteins, functioning as a docking protein. One example is the pro-apoptotic protease activating factor (Apaf-1). Bcl-2 binds to Apaf-1 inhibiting apoptosis.
Agonists for cell death (signaling pathways) lead to mitochondrial permeability by pore formation within the inner and outer membrane which leads to swelling of the mitochondria. Cytochrome c, a key enzyme of cellular respiration, is released into the cytosol. It then disrupts the binding between bcl-2 and pro-apoptotic protease activating factor (Apaf-1). This leads to an initiator caspase which leads to proteolysis (Execution phase).
Thus, bcl-2 inhibits apoptosis by inhibiting the release of cytochrome c and binding and inactivating Apaf-1.
Execution Phase (Final Proteolytic Pathway, Caspases)
The caspases are the mammalian counterpart for the ced-3 gene. The term is a combination of a cysteine protease (c-) and its enzymatic cleavage after aspartic acid residues (-aspase). Initiator caspases bind to Apaf-1 leading to apoptosis. Others like caspase 8, are triggered by Fas-Fas ligand interactions. Once caspases are activated, they initiate a series of enzymatic cleavages of key proteins that are responsible for DNA replication and repair.
Removal of Dead Cells
The cell surface markers of the apoptotic bodies allows for phagocytes to recognize and dispose of them, without the participation of inflammatory cells.
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