Porth's Essentials of Pathophysiology, 4e

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Cellular Responses to Stress, Injury, and Aging

C h a p t e r 2

It also separates the webbed fingers and toes of the developing embryo. Apoptotic cell death occurs in the hormone-dependent involution of endometrial cells dur- ing the menstrual cycle and in the regression of breast tissue after weaning from breast-feeding. The control of immune cell numbers and destruction of autoreactive T cells in the thymus have been credited to apoptosis. Cytotoxic T cells and natural killer cells are thought to destroy target cells by inducing apoptotic cell death. Apoptosis is linked to many pathologic processes and diseases. For example, interference with apoptosis is known to be a mechanism that contributes to carcino- genesis. 27 Apoptosis is also known to be involved in the cell death associated with viral infections, such as hepati- tis B and C. 27,28 Apoptosis may also be implicated in neu- rodegenerative disorders such as ALS, Alzheimer disease, and Parkinson disease. However, the exact mechanisms involved in these diseases remains under investigation. Two basic pathways for apoptosis have been described (Fig. 2-9). These are the extrinsic pathway, which is death receptor dependent, and the intrinsic pathway, which is death receptor independent. The execution phase of both pathways is carried out by proteolytic enzymes called caspases (cysteine proteases that cleave aspartate residues), which are present in the cell as procaspases and are activated by cleavage of an inhibitory portion of their polypeptide chain. 2,29 The extrinsic pathway involves extracellular signaling proteins that bind to cell surface molecules called death receptors and trigger apoptosis. The prototype death receptors are tumor necrosis factor (TNF) receptor and the Fas ligand receptor. 29 Fas ligand may be expressed on the surface of certain cells, such as cytotoxic T cells, or appear in a soluble form. When Fas ligand binds to its receptor, proteins congregate at the cytoplasmic end of the Fas receptor to form a death-initiating complex. The complex then converts procaspase-8 to caspase-8. Caspase-8, in turn, activates a cascade of caspases that execute the process of apoptosis. The end result includes activation of endonucleases that cause fragmentation of DNA and cell death. In addition to TNF and Fas ligand, primary signaling molecules known to activate the extrinsic pathway include TNF-related apoptosis- inducing ligand (TRAIL); the cytokine interleukin-1 (IL- 1); and lipopolysaccharide (LPS), the endotoxin found in the outer cell membrane of gram-negative bacteria. The intrinsic pathway, or mitochondrion-induced pathway, of apoptosis is activated by conditions such as DNA damage, ROS, hypoxia, decreased ATP lev- els, cellular senescence, and activation of the p53 pro- tein by DNA damage. The intrinsic pathway is tightly regulated to ensure that cells kill themselves only when appropriate. A major class of intracellular regulators of apoptosis is the Bcl-2 family of proteins. Some of these proteins insert into the mitochondrial membrane open- ing channels through which proteins escape into the cytoplasm. 29 A crucial protein released from the mito- chondria is cytochrome c, a component of the mitochon- drial electron transport chain (see Chapter 1). When released into the cytoplasm, cytochrome c binds to a procaspase-activating protein that activates caspases,

Extrinsic (death receptor–mediated) pathway

Intrinsic (mitochondrial-mediated) pathway

TRAIL

TNF

FasL

LPS

IL-1

Outside cell

Receptor

Inside cell

Death domain

FADD

ROS DNA damage Hypoxia Senescence Low ATP level

Bid

Caspase-9

p53

Bax

Mitochondrion

Cytochrome c

Caspase-3 (–6 or –7)

Caspase-8

Apoptosis

including caspase-3. Caspase-3 activation is a com- mon step to both the extrinsic and intrinsic pathways. Activation of caspase-8 in the extrinsic pathway can also lead to activation of pro-apoptotic proteins, such as Bid and Bax, thereby bridging the two pathways for apoptosis. 2,29 While some members of the Bcl-2 family are pro-apoptotic, others are anti-apoptotic and inhibit apoptosis by binding to pro-apoptotic proteins, either on the mitochondrial membranes or in the cytoplasm. Inhibitors of apoptosis are thought to contribute to cancer and autoimmune diseases. 29–31 The Bcl-2 gene FIGURE 2-9. Pathways for apoptosis.The extrinsic pathway is activated by signals such asTNF-related apoptosis-inducing ligand (TRAIL) and Fas ligand (FasL) that, upon binding to the Fas receptor, form a death-inducing complex by joining the Fas-associated death domain (FADD) to the death domain of the Fas receptor.The intrinsic pathway is activated by signals, such as reactive oxygen species (ROS) and DNA damage, which induce the release of cytochrome c from mitochondria into the cytoplasm. Both pathways activate caspases to execute apoptosis, with activation of the pro-apoptotic proteins Bid and Bax by caspase-8 serving to bridge the two systems. ATP, adenosine triphosphate; DNA, deoxyribonucleic acid; IL-1, interleukin-1; LPS, lipopolysaccharide;TNF, tumor necrosis factor.