1. Apoptosis is programmed cell death marked by cell fragmentation, chromatin condensation, and elimination of apoptotic bodies by phagocytosis. 2. Apoptosis can occur physiologically during development and homeostasis or pathologically due to DNA damage, protein misfolding, and viral infections. 3. Apoptosis is initiated through the intrinsic mitochondrial pathway or extrinsic death receptor pathway and executed via caspase activation, resulting in cytoskeletal and DNA breakdown into apoptotic bodies for phagocytic removal.
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Apoptosis
1. 1
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
2. 2
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
Receptor-ligand
interactions
(Fas, TNF receptor)
Adapter proteins
(FADD)
Activation of Apoptotic sensors
(Bcl-2 family – Bim, Bid, Bad)
Activation of Apoptotic activators
(Bcl-2 family – Bax, Bak)
Insert into mitochondrial membrane
and create channels
EXTRINSIC PATHWAY
(death receptor)
# by
Bcl regulators
(Bcl-2, Bcl-x, Mcl-1)
(# of apoptosis)
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
3. 3
Cyto c in cytoplasm
Cyto C binds to apaf-1 and forms
cytoC-apaf1 complex
Executioner
Caspase
(Caspase 3&6)
complex activates initiator caspase 9
inhibited by
SMAC/DIABLO
(# of apoptosis)
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