6.Apoptosis.pdf

Apoptosis AP DR MIE MIE SEIN MBBS BLOCK 1 Learning outcomes 1. 2. 3. 4. Define apoptosis. (C1) State the causes of physiological and pathological apoptosis. (C1) Describe the mechanisms of apoptosis. (C2) Compare the features of necrosis and apoptosis. (C4) Manipal University College Malaysia 2 Defi...

Apoptosis AP DR MIE MIE SEIN MBBS BLOCK 1 Learning outcomes 1. 2. 3. 4. Define apoptosis. (C1) State the causes of physiological and pathological apoptosis. (C1) Describe the mechanisms of apoptosis. (C2) Compare the features of necrosis and apoptosis. (C4) Manipal University College Malaysia 2 Definition Apoptosis is a pathway of cell death that is induced by a tightly regulated suicide program in which cells destined to die activate intrinsic enzymes that degrade the cells’ own nuclear DNA and nuclear and cytoplasmic proteins. Manipal University College Malaysia 3 Distinctive and important mode of cell death Apoptotic cells break up into fragments (apoptotic bodies) The plasma membrane remains intact but its structure is altered These become “tasty” targets for phagocytosis Does not elicit an inflammatory reaction Programmed cell death It occurs normally in physiologic conditions but also in pathologic conditions: when cells are damaged beyond repair, especially damage affects cells’ DNA Manipal University College Malaysia 4 Causes of Apoptosis Physiologic situations 1. Programmed destruction of cells during embryogenesis implantation, organogenesis, developmental involution and metamorphosis 2. Hormone dependent involution in the adult endometrial cells break down during menstrual cycle 3. Cell loss in proliferating cell populations intestinal crypt epithelium ( homeostasis) 4. Elimination of potentially harmful self-reactive lymphocytes to prevent reactions against one’s own tissues 5. Death of neutrophils in an acute inflammatory response and lymphocytes at the end of an immune response cells undergo apoptosis—deprived of necessary survival signals (growth factor) Manipal University College Malaysia 5 Causes of Apoptosis Pathologic conditions 1. DNA damage: Radiation, cytotoxic anticancer drugs and hypoxia can damage DNA either directly or via production of free radicals 2. Accumulation of misfold proteins: ER stress –basis of several degenerative diseases of the CNS and other organs 3. Cell death in certain infections: particularly viral infections (HIV infection, Viral Hepatitis) 4. Pathologic atrophy in parenchymal organs after duct obstruction: pancreas, parotid gland and kidney 5. Cell death in the tumours (during regression or active growth) Manipal University College Malaysia 6 Morphology Histology Cell shrinkage (increased density of cytoplasm with tightly packed organelles) Chromatin condensation Formation of cytoplasmic blebs and apoptotic bodies Phagocytosis of apoptotic cells or cell bodies, usually by macrophages Apoptosis of an epidermal cell in an immune reaction. The cell is reduced in size and contains brightly eosinophilic cytoplasm and a condensed nucleus Source: Robbins and cotran pathologic basis of disease Manipal University College Malaysia 7 Biochemical Events in Apoptosis Protein cleavage: protein hydrolysis by protease “caspases” breaks up nuclear scaffold and cytoskeleton Protein cross linking: cytoplasmic proteins shrunken cells and break into apoptotic bodies DNA break down: by endonuclease Phagocytic recognition: by expressing phosphatidylserine & thrombospondin on cell membrane Manipal University College Malaysia 8 Mechanism of Apoptosis 4 steps 1. Initiation of apoptosis by activation of signaling pathways: There are two main pathways: (a) Death receptor (Extrinsic ) Pathway (b) Mitochondrial (Intrinsic ) Pathway 2. Control and integration 3. Execution phase 4. Removal of dead cells Source: Robbins and cotran pathologic basis of disease Manipal University College Malaysia 9 Mechanism of Apoptosis Two pathways of apoptosis differ in their induction, regulation and both culminate in the activation of caspases. In the mitochondrial pathway, proteins of the BCL2 family ( regulator protein) which regulate mitochondrial permeability, become imbalanced and leakage of various substances (Cytochrome C and other pro-apoptotic proteins) from mitochondria leads to caspases activation. In death receptor pathway, signals from plasma membrane receptors lead to assembly of adaptor proteins into a “death-including signalling complex” which activate caspases. (lethal signals are controlled by BCL2 family) Proteolytic cascade involving executioner caspases Endonuclease activation Breakdown of cytoskeleton Nuclear fragmentation and cytoplasmic bleb Apoptotic bodies Phagocytosis Manipal University College Malaysia 10 Specific example of apoptosis Fas ligand mediated apoptosis (immune cells - CD95) TNF induced apoptosis ( inflammatory cells) Cytotoxic T lymphocyte stimulated apoptosis ( target cell expressing foreign Ag) Apoptosis after growth factor deprivation (neuron cells: Neurodegenerative diseases) DNA damage mediated apoptosis (Chemotherapy, radiotherapy) Death of virus-infected cells as in AIDS Manipal University College Malaysia (MUCM) 11 Comparism of Necrosis and Apoptosis Characteristics Necrosis Apoptosis Cell size Enlarged (swelling) Reduced (shrinkage) Nucleus Pyknosis →karyorrhexis → karyolysis Fragmentation into nucleosome size fragments Plasma membrane Disrupted Intact; altered structure, especially orientation of lipids Manipal University College Malaysia (MUCM) 12 Characteristics Necrosis Apoptosis Cellular contents Enzymatic digestion; may leak out of cell Intact; may be released in apoptotic bodies Adjacent inflammation Frequent No Physiologic or Pathologic role Invariably pathologic Often physiologic; means of (culmination of irreversible cell eliminating unwanted cells; may be injury) pathologic after some forms of cell injury, especially DNA and protein damage Manipal University College Malaysia (MUCM) 13 References: Robbins and Cotran Pathologic Basis of Disease 10th Edition Manipal University College Malaysia 14 Thank you Manipal University College Malaysia 15