Cell Damage and Death

Question 1

What is Necrosis?

What is Apoptosis?

What is Autophagic cell death?

Answer 1

• Cell death in response to stressors e.g. Ischaemia
• Programmed cell death through a coordinated series of events
• Degradation of normal proteins involved in cellular remodelling, and digestion of abnormal proteins that would otherwise accumulate with toxin exposure

Question 2

NECROSIS:
What’s its function?
→ What does the Failure to do this lead to?

How many cells are affected? Is it a reversible process?

What happens to the cell with Energy Deprivation?

What are the Nuclear changes that occur?

What are the Cytoplasmic changes that occur?

What are the Biochemical changes that occur?

Answer 2

• Remove damaged cells
  → CHRONIC INFLAMMATION
• WHOLE GROUP OF CELLS - Starts out reversible but then becomes irreversible
• Cell unable to produce ATP due to lack of oxygen, and then Swells due to influx of water. Ruptured lysosomes release their enzymes to cause destruction of organelles and nuclear material. Cellular debris stimulates an inflammatory cell response.
• • Chromatin condenses and shrinks
  • Fragmentation of Nucleus
  • Dissolution of Chromatin by DNase causing the basophilic-stained DNA to fade
• • Opacification - Denaturation and aggregation of proteins
  • Complete digestion of cells by enzymes, causing cell to liquify (Liquefactive Necrosis)
• • Release of enzymes (e.g. Creatine Kinase, Lactate Dehydrogenase)
  • Release of proteins (e.g. Myoglobin)

Question 3

Types of Necrosis:
1. Describe Coagulative Necrosis

2. Describe Liquefactive Necrosis
3. Describe Caseous Necrosis
4. Describe Fatty Necrosis
5. Describe Fibrinoid Necrosis

Answer 3

1. Typical in Hypoxic environments - Cell outlines remain after cell death (e.g. MI, Infarction)
2. Cellular destruction and Pus formation (e.g. Pneumonia)
3. Mix of Coagulative and Liquefactive necrosis (e.g. Tuberculosis)
4. Action of lipases on fatty tissues (e.g. Acute Pancreatitis)
5. Immune-mediated vascular damage, marked by deposition of Fibrin-like proteinaceous material in arterial walls, giving it a Smudgy and Acidophilic appearance

Question 4

APOPTOSIS:
What’s its function?

How many cells are affected? Is it a reversible process?

What is it involved in?

What can lead to Intrinsic Apoptosis?

What can lead to Extrinsic Apoptosis?

What are the Nuclear changes that occur?

What are the Cytoplasmic changes that occur?

What are the Biochemical changes that occur?

Answer 4

• Selective process for the deletion of superfluous, infected, or transformed cell
• SINGLE/FEW CELLS - Irreversible once initiated
• Embryogenesis, Metamorphosis, Normal tissue turnover, Endocrine-dependent tissue atrophy, Pathological conditions
• DNA damage, Interruption of cell cycle, Viral Infection
• Withdrawal of Growth factors, T cell activity, Extracellular signals
• • Chromatin condenses on Nuclear membrane
  • DNA cleavage/split
• • Cell shrinks
  • Organelles packed into membrane-bound vesicles - Cell fragmentation as vesicles bud off
  • Phagocytosis of cell fragments by Macrophages and Adjacent cells
  • No leakage of cytosolic components
• • Glycoproteins expressed on surface for Macrophage recognition and Phagocytosis
  • Protein cleavage/split by proteases and caspases

Question 5

Apoptotic Pathway - CASPSASES:
What are Caspases?
→ What are they produced as?

What are the 2 types of Caspases?

What are Initiator Caspases activated by?

What does the activation of Caspases cause?

Answer 5

• Cysteine Aspartate Specific Proteases - Role in the INITIATION OF APOPTOSIS
  → Inactive precursors (PROCASPASES)
• Initiator and Effector Caspases
• INDUCED PROXIMITY
• Shrinkage, Chromatin condensation, DNA fragmentation and Plasma membrane blebbing (Bulging)

Question 6

Cytochrome C-Induced Apoptosis (INTRINSIC Pathway):
What is Cytochrome C released in response to?

Regulation of Cytochrome C Release:
What’s the action of Bcl-2 dimers?
→ How does it do this?

How does Phosphorylated Bad work?

How does Intracellular stress affect Cytochrome C release?

Answer 6

• Oxidative stress by a permeability transition
• Cytochrome C Binding site on Apoptotic Protease Activating Factor (APAF), activation of APAF leads to activation of Caspase Recruitment Domain (CARD), which binds to Procaspases = Death-Inducing Complex
• Anti-Apoptotic
  → Blocks BAX channels, which is Cytochrome C uses to be released from mitochondria
• Dephosphorylated by survival signals (Akt/PKB) - Dephosphorylated Bad then forms Heterodimers with Bcl-2, which makes it unable to block the Bax channels = Cytochrome C release = Apoptosis
• Leads to more Bax channel expression

Question 7

Ligand-Induced Dimerisation (EXTRINSIC Pathway):

How does this work?

Answer 7

• Membrane-bound Ligand binds to a Death Domain, which activates the Death domain on the Death Effector domain - Death effector domain then binds to Procaspases