Apoptosis is a genetically programmed cell-demise process that facilitates the elimination of damaged or unwanted cells in various circumstances, including organ and tissue development during embryogenesis, immune system development and function, normal tissue homeostasis, and tissue healing [35, 36]. Under normal conditions, humans lose millions of cells every day via apoptosis, a process that is balanced by the generation of new cells. Apoptosis can be induced by a large number of internal or external stimuli, including UV irradiation [37], oxidative stress [38], hypoxia [39], cytokines such as tumor necrosis factor (TNF) and Fas ligand (FasL) [40], DNA-damaging drugs [41], drugs of abuse such as cocaine and heroin [42, 43], complement attack [44], nitric oxide [45], inhibitors of survival proteins [46], and natural substances such as lycopene and resveratrol [47, 48].

Apoptotic cells can be distinguished from necrotic cells by their distinctive morphological features (Fig. 6.1), which include general shrinkage, cytoskeleton disruption, cytoplasmic membrane blebbing, nuclear membrane solubilization, and chromatin margination and fragmentation [9, 35, 36]. A hallmark feature of apoptosis is the fragmentation of the dying cell into numerous blebs or apopto-tic bodies, which in the early stages of the death process remain surrounded by a relatively impermeable cytoplasmic membrane. Retention of cytoplasmic membrane integrity is important for the exposure of membrane signals such as

Stages Apoptosis
Fig. 6.1 Key events associated with the progression of apoptosis and necrosis.

the externalization of phosphatidylserine, which in essence sends a message to phagocytic cells to "eat me now or else" [49]. These signals are essential for facilitating recognition and processing of dying cells by phagocytes. This recognition process normally occurs swiftly; otherwise, apoptotic cells or bodies that linger for too long will eventually lose their cytoplasmic membrane integrity and develop secondary necrosis [49]. Secondary necrosis in turn leads to the release of noxious intracellular contents, such as proteases, nucleases, and proinflam-matory "danger" signals, that could not only damage the surrounding tissue but also provoke a localized inflammatory response [50]. The efficient clearance of apoptotic cells is therefore a protective mechanism operating in higher organisms to prevent unnecessary inflammatory responses.

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