Apoptosis

READ IN LANDSCAPE MODE

Questions

• Molecular mechanism
• Apoptosis Vs Necrosis

Definition

Apoptosis is a form of genetically programmed cell death which eliminates unwanted host cells.

Types

• Types of Apoptosis-
  • Physiological Apoptosis-
    • Post Inflammatory apoptosis of neutrophils and lymphocytes
    • Hormone dependent involution like in breasts.
    • During implantation and organogenesis- embryogenesis
    • Cellular ageing
    • Thymus
  • Pathological Apoptosis-
    • DNA damage and mutation
    • Viral infections
    • Unfolded/Misfolded proteins during ER stress
    • Duct obstruction causing pathological atrophy as in Salivary gland, pancreas.

Phases

• Phases Of Apoptosis- Apoptosis takes place in 2 phases-
  • Initiator Phase- Can be of two types-
    • Extrinsic– Cell Membrane, Caspase 8 & 10 involved
    • Intrinsic– Mitochondrial, Caspase 9 involved
  • Execution Phase– Caspase 3,6 involved

Morphological Changes

Intrinsic Mechanism

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• Unrepairable DNA damage triggers p53
• Decreased activity of Anti-apoptotic protein BCL-2
• Increased activity of Pro-apoptotic protein BAX and BAK
• Mitochondrial permeability increases
• Cytochrome c escapes from Mitochondria into cytoplasm
• Increases Activity of APAF-1
• Initiator Phase
• Increased Activity of Caspase 9, 10.
• Executionary Phase
• Increased Activity of Caspase 3, 6 & 7
• Increased activity of protease and Nuclease
• Cell Death

Extrinsic Mechanism

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Also known as Death Receptor Pathway

• Extracellular Signals
• Receptor-Ligand Interactions (Fas-Fas ligand, TNF-TNF Receptor)
• Binding of Fas to Fas-L
• Adaptor Proteins
• Activation of Initiator Caspase 8, 10
• Activation of Executioner Caspase 3, 6
• Nuclear fragmentation
• Formation of Cytoplasmic Blebs
• Phagocytosis

Apoptosis Vs Necrosis

Apoptosis	Necrosis
Programmed Cell Death	Cell death causing an inflammatory response
Can be physiological or pathological	Is always pathological
Not associated with inflammation, hence neutrophils absent	Associated with adjacent inflammation, hence neutrophils present.
Step Ladder dUTP pattern	Smear dUTP pattern
Single cell or small groups of cells are involved	Large groups of cells, tissues or organs are involved
Cell Shrinkage	Cell Swelling
Plasma Membrane is intact	Plasma membrane is disintegrated
Chromatin undergoes condensation under nuclear membrane(Pyknosis)	Chromatin undergoes pyknosis, karyorrhexis, and karyolysis
Clinical Marker is Annexin V Staining	Clinical Marker is Increased LDH and other intracellular components in the extracellular space.

Variants of Apoptosis

Necroptosis

• Programmed necrosis
• Leaking of intracellular contents after cell death is internally regulated or progammed
• Similar to Necrosis: Biochemically and Morphologically
• Similar to Apoptosis: At molecular level
• Does not involve caspase activation

Examples-

• Formation of bony growth plate
• Viral defense mechanism
• Steatohepatitis
• Inflammatory diseases like Crohns, Pancreatitis

Pyroptosis

• Apoptosis associated with the release of fever producing cytokine interleukin 1.
• Triggered by cytoplasmic entry of inflammasomes
• Inflammasomes are multi protein cytosolic proteins regulating the activation of Caspase and inducing inflammation by expression of pro inflammatory cytokines.
• There is cellular swelling and damage to plasma membrane
• Cell death is brought about by activation of Caspase 1 or interleukin 1 beta converting enzyme or ICE. Another enzyme is Caspase 11 which generates interleukin 1.

Ferroptosis

• Iron dependent pathway of cell death by lipid metabolism.
• Loss of mitochondrial cristae
• Mitochondrian outermembrane is ruptured
• Clinical: Iron Supplements are not given to patients with inflammation.