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General Pathology Notes (Robbins)

By Dr. Ashish Jawarkar Chapter 1 : CELLULAR RESPONES TO STRESS AND TOXIC INSULTS: ADAPTATION, INJURY AND CELL DEATH

TOPIC 1. APOPTOSIS aka Programmed cell death OVERVIEW 1. definition 2. causes 1 physiologic 2 pathologic 3. morphology 1 Light microscopy 2 Electron Microscopy 4. Mechanisms 1. Initiation a. Intrinsic pathway b. extrinsic pathway 2. Execution 3. Removal of dead cells 5. Disorders of dysregulated apoptosis

* Definition 1. a pattern of cell death 2. affecting single cells 3. marked by fragmentation into cell membrane bound apoptotic bodies, Condensation of chromatin 4. these apoptotic bodies are eliminated by phagocytosis * Causes of Apoptosis Physiologic 1.During embryogenesis implantation, organogenesis, involution and metamorphosis 2. Due to hormone withdrawl - endometrial cycle - ovarian follicular atresia at menopause - breast after weaning - prostate after castration 3. In homeostasis - lymphocytes that recognize self antigens - epithelial cells in intestinal crypts - neutrophils and lymphocytes at the end of immune response Pathologic 1. DNA damage due to radiation/hypoxia/ Anticancer drugs 2. Accumulation of misfolded proteins ER stress - apoptosis This is the basis of degenerative diseases of the CNS 3. Certain viral infections lead to cell death by apoptosis like adenovirus, HIV and hepatitis

4. Atrophy of parenchymal organs after duct obstruction pancreas, parotid, kidney * Morphology
Notes on apoptosis.. By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes

LIGHT MICROSCOPY Apoptotic bodies seen as 1. shrunken cell 2. no damage to plasma membrane 3. intensely eosinophilic cytoplasm 4. dense nuclear chromatin 5. no inflammation ELECTRON MICROSCOPY 1. intact nuclear membrane 2. chromatin condensation under nuclear membrane 3. formation of cytoplasmic blebs * Mechanisms Initiation execution clearing of dead cells INITIATION

INTRINSIC PATHWAY (mitochondrial) Cell injury due to 1. growth factor withdrawl 2. ROS 3. Toxins 4. Protein misfolding 5. radiation

EXTRINSIC PATHWAY (death receptor)

Receptor-ligand interactions (Fas, TNF receptor)

Activation of Apoptotic sensors (Bcl-2 family Bim, Bid, Bad) # by Bcl regulators (Bcl-2, Bcl-x, Mcl-1) (# of apoptosis)

Adapter proteins (FADD)

Activation of Apoptotic activators (Bcl-2 family Bax, Bak) Insert into mitochondrial membrane and create channels

Initiator caspases (Caspase 8, in human caspase 10)

Mitochondrial cyto-c leakage

Notes on apoptosis.. By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes

Cyto c in cytoplasm

Cyto C binds to apaf-1 and forms cytoC-apaf1 complex

Executioner Caspase (Caspase 3&6) inhibited by SMAC/DIABLO (# of apoptosis)

complex activates initiator caspase 9

caspase 9 activates executioner caspase 3

Endonuclease activation

Breakdown of cytoskeleton

DNA fragmentation

Formation of cytoplasmic blebs and apoptotic bodies

Phagocytosis of apoptotic bodies Removal of dead cells The apoptotic bodies are recognized by phagocytes by 1. alterations in plasma membrane 2. thrombospondin is expressed on the outer leaflet 3. coatin with complements eg. C1q * disorders of dysregulated apoptosis 1. disorders due to too little apoptosis - cancer - autoimmune disorders 2. disorders due to too much apoptosis - neurodegenerative diseases
Notes on apoptosis.. By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes