Figure 269

Schematic diagram of changes occurring in necrosis and apoptosis.

This diagram shows the major steps in necrosis and apoptosis. In necrosis (left column), breakdown of the cell membrane results in an influx of water and extracellular ions, causing the organelles to undergo irreversible changes. Lysosomal enzymes are released into the extracellular space, causing damage to neighboring tissue and an intense inflammatory response. In apoptosis (right column), the cell shows characteristic morphologic and biochemical features such as DNA fragmentation, decrease in cell volume, membrane blebbing without loss of membrane integrity, and formation of apoptotic bodies, causing cell breakage. Apoptotic bodies are later removed by phagocytotic cells without inflammatory reactions.

to change its physical and chemical properties and lead to blebbing without loss of membrane integrity (see Fig. 2.69).

• Formation of apoptotic bodies, the final step of apoptosis, results in cell breakage (Fig. 2.70). These membrane-bounded vesicles originate from the cytoplasmic bleb containing organelles and nuclear material. They are rapidly removed by phagocytotic cells. The removal of apoptotic bodies is so efficient that no inflammatory response is elicited.

Apoptosis is regulated by external and internal stimuli

Apoptotic processes can be activated by a variety of external and internal stimuli. Some factors, such as tumor necrosis factor (TNF), acting on cell membrane receptors, trigger apoptosis by recruiting and activating the caspase cascade. Consequently, the TNF receptor is known as the "death receptor." Other external activators of apoptosis include transforming growth factor (3 (TGF-/3), certain neurotransmitters, free radicals, oxidants, and UV and ioning radiation. Internal activators of apoptosis include oncogenes (e.g., myc and vel), tumor suppressors such as p53, and nutrient deprivation antimetabolites (Fig. 2.71).

Apoptosis can also be inhibited by signals from other cells and the surrounding environment via so-called survival factors. These include growth factors, hormones such as estrogen and androgens, neutral amino acids, zinc, and interactions with extracellular matrix proteins. However, the most important regulatory function in apoptosis is ascribed to internal signals from the Bcl-2 family of proteins. Members of this family consist of an-tiapoptotic and proapoptotic members that determine the life or death of a cell. These proteins interact with each other to suppress or propagate their own activity by acting on downstream activation of various executional steps of apoptosis. They also act independently on mitochondria to regulate the release of cytochrome c, the most potent apoptosis-inducing agent.

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