Fig.2.3 .Apoptotic body Phagocyte Phagocytosis of apoptotic cells and fragments NORMALCELLAPOPTOSIS
Table 2.2 Physiologic and Pathologic Conditions Associated With Apoptosis
Condensation of chromatin
Table 2.2 ). It also occurs as a pathologic event when cells are damaged, especially when the damage affects the cell’s DNA or proteins; thus, the irreparably damaged cell is eliminated.
• Physiologic apoptosis. During normal development of an organism, some cells die and are replaced by new ones. In mature organisms, highly proliferative and hormone-responsive tissues undergo cycles of proliferation and cell loss that are often determined by the levels of growth factors. In these situations, the cell death is always by apoptosis, ensuring that unwanted cells are eliminated without eliciting potentially harmful inflammation. In the immune system, apoptosis eliminates excess leukocytes left at the end of immune responses as well as lymphocytes that recognize self-antigens and could cause autoimmune diseases if they were not purged.
TurnoverofproliferativetissuesLossofgrowthfactorsignaling(e.g.,intestinalepithelium,(presumedmechanism)lymphocytesinbonemarrow,andthymus) • Apoptosis in pathologic conditions. Apoptosis eliminates cells that are damaged beyond repair. This is seen when there is severe DNA damage, for example, after exposure to radiation and cytotoxic drugs. The accumulation of misfolded proteins also triggers apoptotic death; the underlying mechanisms of this cause of cell death and its significance in disease are discussed later, in the context of ER stress. Certain infectious agents, particularly some viruses, induce apoptotic death of infected cells.
Mechanisms of Apoptosis
Apoptosis is regulated by biochemical pathways that control the balance of death-and survival-inducing signals and ultimately the activation of enzymes called caspases. Caspases were so named because they are cysteine proteases that cleave proteins after aspartic acid residues. Two distinct pathways converge on caspase activation: the mitochondrial pathway and the death receptor pathway (
Fig. 2.12 ). Although these pathways can intersect, they are generally induced under different conditions, involve different molecules, and serve distinct roles in physiology and disease. The end result of apoptotic cell death is the clearance of apoptotic bodies by phagocytes.
• The mitochondrial (intrinsic) pathway seems to be responsible for apoptosis in most physiologic and pathologic situations. Mitochondria contain several proteins that are capable of inducing apoptosis, including cytochrome c. When mitochondrial membranes http://ebooksmedicine.net
PhagocyteMitochondria Receptor-ligand interactions • Fas • TNF receptor Cell injury • Growth factor withdrawal • DNA damage (by radiation, toxins, free radicals) • Protein misfolding (ER stress) Cytochrome c and other pro-apoptotic proteins Regulators (Bcl-2, Bcl-xL) Caspase activation Adaptor proteins Breakdown of cytoskeleton Endonuclease activation Ligands for phagocytic cell receptors Apoptotic body Nuclear fragmentation BH3 sensors Bcl-2 family effectors (Bax, Bak)