Apoptosis PDF - UMM AL-QURA UNIVERSITY

Apoptosis Prof. Ghada Esheba Pathology Department Objectives Identify apoptosis and enumerate its different physiological and pathological causes Describe biochemical features and mechanism of apoptosis Summarize the role of Apoptosis in health and disease 2 ©UQ...

Apoptosis Prof. Ghada Esheba Pathology Department Objectives Identify apoptosis and enumerate its different physiological and pathological causes Describe biochemical features and mechanism of apoptosis Summarize the role of Apoptosis in health and disease 2 ©UQUMed, Year 3 04/03/17  Apoptosis sinuat - Apoptosis is a pathway of cell death in which cells activate enzymes that - degrade the cells’ own nuclear DNA and nuclear and cytoplasmic -- - proteins Fragments of the apoptotic cells then break off, giving the appearance that is responsible for the name (apoptosis, “falling off ”).  Apoptosis The plasma membrane of the apoptotic cell remains intact, but the membrane is altered so the cell and its fragments become targets for phagocytes. The dead cell is rapidly cleared before its contents have leaked out, and therefore cell death by this pathway DOES NOT cause inflammation  Physiological Apoptosis A normal phenomenon serves to eliminate cells that are no longer needed and to maintain a steady number of various cell populations in tissues. e.g. 1. The programmed destruction of cells during embryogenesis 2. Involution of hormone-dependent tissues 3. Cell loss in proliferating cell populations 4. Death of cells that have served their useful purpose (neutrophils and lymphocytes) 5. Elimination of potentially harmful self-reactive lymphocytes  Apoptosis in Pathologic Conditions Apoptosis eliminates cells that are genetically altered or injured 1. DNA damage: by ??? 2. Accumulation of misfolded proteins 3. Cell injury in certain infections, particularly viral infections Morphology Apoptotic cells appear as round or oval masses with intensely eosinophilic cytoplasm Nuclei show chromatin condensation and karyorrhexis The cells rapidly shrink, form cytoplasmic buds, and fragment into apoptotic bodies composed of membrane-bound vesicles of cytosol and organelles These fragments are quickly phagocytosed without eliciting an inflammatory response Mechanisms of Apoptosis Activation of enzymes called caspases Activated caspases activation of nucleases that degrade DNA and other enzymes that destroy nucleoproteins and cytokeletal proteins. The activation of caspases depends on a balance between pro- and anti- apoptotic molecular pathways. Two distinct pathways leads to caspase activation: 1. Mitochondrial (intrinsic) pathway 2. Death receptor (extrinsic) pathway Mitochondrial (intrinsic) pathway Mitochondria contain several proteins that are capable of inducing apoptosis; these proteins include cytochrome c The choice between cell survival and death is determined by the permeability of mitochondria Mitochondrial permeability is controlled by a family of proteins, the prototype of which is Bcl-2 (anti-apoptotic). Mitochondrial (intrinsic) pathway When cells are deprived of growth factors, or are exposed to agents that damage DNA activation of pro-apoptotic Bax and Bak Bax and Bak insert into the mitochondrial membrane, and form channels through which cytochrome c and other mitochondrial proteins escape into the cytoplasm Cytochrome c activates caspase-9  The Death Receptor (Extrinsic) Pathway of Apoptosis Many cells express surface molecules, called death receptors, that trigger apoptosis. Type I TNF receptor and Fas (CD95). Fas-ligand (FasL) is a membrane protein expressed mainly on activated T lymphocytes. When these T cells recognize Fas-expressing targets, Fas molecules are cross- linked by the FasL which in turn bind caspase-8 leads to their activation, thus initiating the caspase cascade. Clearance of Apoptotic Cells Apoptotic cells undergo changes in their membranes that promote their phagocytosis. In normal cells phosphatidylserine is present on the inner leaflet of the plasma membrane In apoptotic cells this phospholipid "flips" out and is expressed on the outer layer of the membrane Recognized by macrophages and leads to phagocytosis of the apoptotic cells. Evasion of apoptosis Evasion of cell death by cancers is mainly due to interfere with the intrinsic pathway of apoptosis. The most common abnormalities are: 1. loss of p53 function, either by TP53 mutations or overexpression of the p53 inhibitor MDM2. 2. overexpressing anti-apoptotic members of the BCL2 family, such as BCL2 Evasion of apoptosis Role of BCL2 in protecting tumor cells from apoptosis. 85% of follicular lymphomas carry a characteristic t(14;18) which leads to overexpression of the BCL2 protein. Overexpression of the BCL2 protects the lymphocytes from apoptosis and allow them to survive for long periods producing accumulation of lymphocytes resulting in lymphadenopathy 17 Evasion of apoptosis Inhibitors of MDM2 (which activate p53) and inhibitors of BCL2 family members induce the death of cancer cells by stimulating the intrinsic pathway of apoptosis and are being developed as therapeutic agents.  Features of Necrosis and Apoptosis Feature Necrosis Apoptosis Cell size Enlarged (swelling) Reduced (shrinkage) Nucleus Pyknosis Fragmentation into nucleosome size fragments Karyorrhexis karyolysis Plasma Disrupted Intact; altered structure, especially orientation of lipids membrane Cellular contents Enzymatic digestion; may leak out Intact; may be released in apoptotic bodies of cell Adjacent Frequent No inflammation Physiologic or Invariably pathologic (culmination Often physiologic, means of eliminating unwanted cells; pathologic role of irreversible cell injury) may be pathologic after some forms of cell injury, especially DNA damage Any Question ? Reference: Robbins Basic Pathology 9th edition Chapter 1 (pages 18- 22) https://www.youtube.com/watch?v=wREkXDiTkPs