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Flashcards in Cell Damage and Cell Death Deck (45)
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1

What are the causes and mechanisms of cell death? 

  • GENETIC:
    • - Abnormal chromosomes (deletions/translocatioNs)
    • - Increased fragility (Fanconi's anaemia)
    • - Failure of repair (Xeroderma pigmentosa)
    • - Inborn errors (Storage disorders ie. Tay Sachs disease)
  • INFLAMMATION:
    • - Trauma
    • - Thrombo-embolism
    • - Atherosclerosis
    • - Vasculitis
  • PHYSICAL:
    • - Irradiation
    • - Heat
    • - Cold
    • - Barotrauma
  • TRAUMATIC DAMAGE:

- Interruption of blood supply
- Direct rupture of cells
- Entry of foreign agents

  • INFECTION:
    • - Toxic agents
    • - Competition for nutrients
    • - Intracellular replication (viruses/mycobacteria provoking an immune response)

CHEMICAL:

  • - Acids/corrosives
  • - Specific actions e.g. enzymes
  • - Interference with metabolism e.g. alcohol

2

What are the three mechanisms of cell death? 

  1. Necrosis 
  2. Apoptosis 
  3. Autophagic Cell Death 

3

Describe necrosis 

Most common cause of cell death due to stresses such as ischaemia, trauma and chemical injury 

4

Describe apoptosis 

Programmed cell death, eliminating unwanted host cells through activation of a co-ordinated, internally programmed series of events effected by a dedicated set of gene products 

5

Describe autophagic cell death 

Process whereby cells engulf parts of themselves 

(degradation of normal proteins involved in cellular remodelling found during metamorphis, ageing and differentiation and for digestion and removal of abnormal proteins which would accumulate following toxin exposure, cancer or disease)

 

Example is breast cancer cell death induced through tamoxifen 

6

What is the cause of necrosis? 

Lack of blood supply to cells or tissues 

due to

  • injury
  • infection
  • cancer
  • infarction
  • inflammation

7

Steps in necrosis

Lack of blood supply = no oxygen

  1. Energy deprivation causes changes (cells unable to produce ATP due to oxygen deprivation)
  2. ATP is required for ion pumps to work; electrolyte levels are imbalanced causing water to enter the cell and cause swelling
  3. Sometimes ion pumps will restore the imbalance and return back to a normal state (reversible)
  4. However, water influx can cause disintegration and bursting, (haphazard destruction) of organelles and nuclear material (irreversible)  
  5. Lysosomes can release their proteases and lipases which can attack nearby cells 
  6. Cellular debris will stimulate an inflammatory response!!

8

What is the microscopic appearance of necrosis?  (Nuclear Changes) 

  • Nuclear changes 
    • Chromatin condensation 
    • Fragmentation of nucleus 
    • Dissolution of chromatin by DNAse 

9

What is the microscopic appearance of necrosis? (Cytoplasmic changes) 

  1. Opacification: denaturation of proteins with aggregation
  2. Complete digestion of cells by enzymes causing cell to liquify (liquefactive necrosis)

10

What is the microscopic appearance of necrosis (chemical changes)? 

  • Release of enzymes such as creatine kinase or lactate dehydrogenase
  • Release of proteins such as myoglobin
    • Biochemical changes are useful in the clinic to measure the extent of tissue damage

11

What is the main function of necrosis? 

What can failure of necrosis lead to? 

Removal of damaged cells from an organism, failure of necrotic cell debris may lead to chronic inflammation!!!

12

What type of cells are selected in apoptosis? 

  • Selective process for the deletion of superfluous, infected or transformed cells

13

Provide examples of processes in which apoptosis is involved in

  • Embryogenesis 
  • Metamorphis 
  • Normal tissue turnover
  • Endocrine-dependant tissue atrophy
    • Cells of the mammary gland atrophy once they are no longer required 
  • Variety of pathological conditions 

14

Give some examples of apoptosis

  • Cell death in hand to form individual fingers 
  • DNA damage mediated apoptosis 
    • DNA damage due to chemo/radiation will cause p53 tumour supressor gene to accumulate. Causes cell cycle arrest allowing for the cell to repair damage 
  • Cell death in tumours causing regression 
  • Cell death in viral diseases 
  • Cell death induced by cytotoxic T-cells 
  • Death of neutrophils during inflammatory response 
  • Death of immune cells 
    • T + B lymphocytes after depletion of cytokines as well as death of autoreactive T cells in developing thymus 

15

What are the two types of apoptosis? 

Intrinsic and Extrinsic 

16

Describe intrinsic apoptosis 

Apoptosis triggered by intracellular signals 

  • DNA damage -p53 dependant pathway 
  • Interruption of the cell cycle 
  • Inhibition of protein synthesis 
  • Viral infection 
  • Change in redox 

 

17

Describe extrinsic apoptosis 

Apoptosis triggered by extracellular signals 

  • Withdrawal of growth factors
  • Extracellular signals e.g TNF 
  • T cells or Natural Killer e.g granzyme 

18

What is the initiator of apoptosis? 

Apoptosis is induced by a family of proteases called CASPASES 

19

What are caspases? 

Cysteine aspartate specific proteases which cleave between cysteine and aspartate amino acid residues 

20

In what form are most proteases synthesised? 

As inactive precursors requiring activation 

= usually partial activation by another protease 

21

What is apoptosis mediated by? 

INTRACELLULAR PROTEOLYTIC CASCADE 

  • Inactive procaspase Y is activated by active caspase X by cleavage N-terminal and C-terminal cleavage sites 
  • As a result of the cleavage, two parts of the procaspase Y will dimerise forming active caspase Y 
  • Active caspase Y (initiator caspase 8 or 9) will go on to degrade further substrates 

22

What happens once the active caspase 8 or 9 has been activated? 

  • The active initiator caspases (8/9) will go to activate other procaspases which will cause cleavage of cytosolic proteins containing cysteine or aspartate 
    • E.g actin cytosolic skeleton breaks down = cell collapse 
  • Further caspases will be activated (caspase 1, 3, 6, 7) which will cause amplification of proteolysis 
    • For example cleavage of nuclear lamin protein essential for nuclear envelope 

23

What are morphological changes that occur as a result of apoptosis? 

Caspase activation will lead to: 

  • Cell shrinkage, Chromatin condensation, DNA fragmentation and plasma membrane blebbing 
  • Actin cytoskeleton will be lost during apoptosis, cells become more rounded and detach from their surface flpating in medium 

24

Why is there no inflammatory response in apoptosis? 

  • Cells will start forming blebs (vesicle membranes) these will bud from the cell and express new molecules which are recognised by phagocytes/macrophages that engulf and digest them 

25

How can you asses whether cells have been undergone apoptosis or necrosis via gel electrophoresis? 

  • Apoptotic Cell DNA = clear laddering 
    • Nucleosomes will remain intact BUT DNAses will cleave around nucleosome = laddering 
  • Necrotic Cell DNA = no laddering 
    • DNA fragmentation = random due 
      • There will be no nucleosomes as they will be denatured due to release of enzymes from lysosomes 

26

Describe the microscopic nuclear changes in apoptosis 

  1. Nuclear chromatin condenses on nuclear membrane 
  2. DNA cleavage 

27

Describe the microscopic cytoplasmic changes that occur in apoptosis 

  1. Shrinkage of cell, organelles packed into membrane vesicles 
  2. Cell fragmentation = membrane bound vesicles bud off 
  3. Phagocytosis of cell fragments by macrophage and adjacent cell 
  4. No leakage of cytosolic components 

28

What are the microscopic biochemical changes that occur in apoptosis? 

  1. Expression of charged sugar molecules on outer surface of cell membrane (recognised by macrophages to enhance phagocytosis) 
  2. Protein cleavage by proteases, caspases 

29

How is the first initiator caspase activated? 

INDUCED PROXIMITY 

This can occur two ways: 

  1. In response to receptor dimerisation upon ligand binding (ligand induced dimerisation) = EXTRINSIC 
  2. Cytochrome C release from mitochondria = INTRINSIC 

30

What are the key molecules in the extrinsic apoptotic pathway? 

Transmembrane receptor = two domains, extracellular ligand binding domain + intracellular death domain 

Death adaptor protein = Two domains death domain and death effector domain. Death domain will form dimers with the death domain of transmembrane receptor 

Procaspase 8 = Two domains, a protease domain and death effector domain. Death effector domain can interact with death effector domain on death adaptor protein 

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