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Clinical Pathology > Cell Death And Cell Damage > Flashcards

Cell Death And Cell Damage Flashcards

1
Q

What are the 6 causes of cell damage/death?

A
  1. Genetic
  2. Inflammation
  3. Physical
  4. Traumatic damage
  5. Infection
  6. Chemical
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2
Q

What are the mechanisms for genetic cell death/damage?

A

Abnormal number of chromosomes (aneuploidy)
Abnormal chromosomes (deletions/insertions)
Increased fragility (Fanconi’s anaemia)
Failure of repair (Xeroderma pigmentosa)
Inborn errors (storage disorders i.e Tay Sachs disease)

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3
Q

What are the mechanisms for inflammation causing cell death/damage?

A
  1. Trauma
  2. Thrombo-embolism
  3. Atherosclerosis
  4. Vasculitis
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4
Q

What are the mechanisms of physical cell death/damage?

A
  1. Irradiation
  2. Heat
  3. Cold
  4. Barotrauma
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5
Q

What are the mechanisms for traumatic damage causing cell death/damage?

A
  1. Interruption of blood supply
  2. Direct rupture of cells
  3. Entry of foreign agents
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6
Q

What are the mechanisms for infection causing cell death/damage?

A
  1. Toxic agents
  2. Competition for nutrients
  3. Intracellular replication (viruses/myobacteria provoking an immune response)
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7
Q

What are the mechanisms for chemicals causing cell death/damage?

A
  1. Acids/corrosives
  2. Specific actions e.g enzymes
  3. Interference with metabolism e.g alcohol
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8
Q

What are the three mechanisms that cause cell death?

A
  1. Necrosis
  2. Apoptosis
  3. Autophagic cell death
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9
Q

What is apoptosis?

A

This is programmed cell death. It eliminates unwanted host cells through activation of coordinated, internally programmed series of events caused by a dedicated set of gene products.

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10
Q

What is autophagic cell death?

A

Degradation of normal proteins involved in cellular remodelling found during metamorphosis, aging and differentiation. Also removes abnormal proteins that would accumulate due to toxin exposure, cancer or disease. E.g death of breast cancer cells induced by tamoxifen.
(Self engulfing/killing)

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11
Q

What is necrosis?

A

Death of groups of cells. Caused by stresses such as ischemia, trauma, chemical injury (result of an injurious agent or event). Causes oxygen deprivation.

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12
Q

What does it mean by necrosis being ‘reversible’ and then ‘irreversible’?

A

During necrosis, ion channels stop working due to ATP not being produced - this means water and electrolytes can’t be balanced and causes swelling of cells and organelles such as mitochondria and nucleus.
If this is fixed before too many things are damaged then the cell water and ion content may be balance again and cell may be functional (reversible).
However, if it is very damaged, then it can’t be repaired hence it bursts and is non functional and dies.

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13
Q

What are the causes of necrosis?

A

Usually due to lack of blood supply to tissue

  1. Injury
  2. Infection
  3. Cancer
  4. Infarction
  5. Inflammation
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14
Q

Explain in detail what happens to cells during necrosis

A
  1. Energy deprivation causes changes (e.g cells unable to produce ATP because of oxygen deprivation)
  2. Cells swell due to influx of water (as ATP is needed for ion channels to work)
  3. Haphazard destruction of organelles and nuclear material by enzymes from ruptured lysosomes
  4. Cellular debris from lysed cell recruits inflammatory mediators and macrophages to remove cellular debris - inflammatory cell response.
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15
Q

What would be the microscopic nuclear changes of necrosis?

A
  1. Chromatin condensation/shrinkage
  2. Fragmentation of nucleus
  3. Dissolution of chromatin by DNAse
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16
Q

What would be the microscopic changes of cytoplasm in necrosis?

A
  1. Opacification : denaturation of proteins with aggregation
  2. Complete digestion of cells by enzymes causing cell to liquify (liquefactive necrosis)
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17
Q

What are the biochemical changes in necrosis?

A
  1. Release of creatine kinase or lactate dehydrogenase (for anaerobic respiration)
  2. Release of proteins such as myoglobin

These are important to measure in the clinic to see the extent of tissue damage.

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18
Q

What is the function of necrosis?

A

Removes damaged cells from an organism. Failure to do so may lead to chronic inflammation.

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19
Q

Give an example of necrosis

A

Astrocytoma

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20
Q

What are the functions of apoptosis?

A

Selective process for removal of unnecessary, mutated, infected or transformed cells.

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21
Q

When is apoptosis involved?

A
  1. Embryogenesise
  2. Metamorphosis
  3. Normal tissue turnover
  4. Endocrine-dependent tissue atrophy
  5. Variety of pathological conditions
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22
Q

What are examples of apoptosis?

A
  1. Cell death in embryonic hand to form individual fingers
  2. Apoptosis induced by growth factor deprivation (neuronal death from lack of NGF)
  3. DNA damage-mediated apoptosis. If DNA is damaged due to radiation or chemotherapeutic agents, p53 (tumour suppressor gene product) accumulates which arrests the cell cycle enabling repair of damage. If repair process fails then p53 triggers apoptosis.
  4. Cell death in tumours causing regression
  5. Cell death in viral diseases (ie hepatitis)
  6. Cell death induced by cytotoxic T cells (ie. cellular immune rejection or graft vs host disease)
  7. Death of neutrophils during acute inflammatory response
  8. Death of immune cells (T and B lymphocytes) after depletion of cytokines.
  9. Death of autoreactive T cells in the developing thymus
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23
Q

Why is apoptosis important in frogs?

A

It helps eliminate the tail during the metamorphosis of a tadpole into a frog

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24
Q

What are the factors influencing the balance of life and death at the cellular level?

A

Survival = growth factors, cytokines, cell-cell and/or cell-matrix contacts

Apoptosis = death domain ligands, DNA damaging agents, lack of growth factors, disruption of cell-cell and/or cell-matrix contacts

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25
Q

What are the two types of apoptosis?

A

Intrinsic and extrinsic

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26
Q

What is intrinsic apoptosis?

A
  1. DNA damage - p53 dependent pathway
  2. Interruption of cell cycle
  3. Inhibition of protein synthesis
  4. Viral infection
  5. Change in redox state
27
Q

What is extrinsic apoptosis?

A
  1. Withdrawal of growth factors (e.g IL3)
  2. Extracellular signals (e.g TNF)
  3. T cell or NK (natural killer) (e.g granzyme)
28
Q

What are caspases?

A

Cysteine Aspartate-specific proteases.

They are cysteine proteases that play a central role in initiation of apoptosis.
Most caspases are synthesises as inactive precursors. They need to be activated (usually partial digestion by another protease)

29
Q

What happens to partial pressure of oxygen and the pH as the distance from the vessel increases?

A

As the distance from the vessel increases, the oxygen levels start to decrease (as it’s getting used) and the pH start decreases due to the production of carbon dioxide.

30
Q

Explain procaspase activation

A

Inactive procaspase Y is activated by cleavage into active caspase Y. This activation is carried out by active caspase X.
It is regulated by the cleavage sites of procaspase Y.

In the activation, the prodomain is removed and we’re left with large and small subunits (dimer).

31
Q

What is the caspase cascade?

A

Active initiator caspase (e.g 8 and 9) activates another type of caspases which are effector caspases (e.g 1,3,6,7). These then activate even more other effector caspases.

E.g some may cleave cytosolic proteins; some may cleave nuclear lamin.
When they cleave cytosolic proteins e.g actin filaments, cell becomes more rounded, loses shape. Apoptosis

32
Q

What does activation of caspases cause?

A

Leads to morphological changes of cell such as shrinkage, chromatin condensation, DNA fragmentation and plasma membrane blebbing.

33
Q

What are blebs?

A

This is the membrane bulging out due to degradation of cytoskeletal filaments. They can contain intact organelles such as mitochondria.
Blebs eventually bud off and are recognised by phagocytes and macrophages. Doesn’t induce an inflammatory response.

34
Q

How does apoptotic cell’s DNA look in gel electrophoresis?

A

You get a ladder of DNA due to cleavage of DNA between nucleosomes. Nucleosomes stay in tact so the DNA wrapping around the nucleosomes is protected which gives this ladder of DNA on the gel.

35
Q

How does a necrosed tissue’s DNA look on a gel electrophoresis?

A

In necrosis, nucleosomes are damaged/denatured so enzymes cut DNA randomly, even those wrapping around nucleosomes. Hence you don’t get a ladder.

36
Q

Give a summary of apoptosis

A
  1. Single or few cells selected
  2. Programmed cell death
  3. Irreversible once initiated
  4. Events are energy driven
  5. Cells shrink as the cytoskeleton is disassembled
  6. Orderly packaging of organelles and nuclear fragments in membrane bound vesicles
  7. New molecules expressed on vesicle membrane stimulate phagocytosis. No inflammatory response.
37
Q

What are the nuclear changes in microscopic appearance of apoptosis?

A
  1. Nuclear chromatin condenses on nuclear membrane

2. DNA cleavage

38
Q

What are the cytoplasmic changes in microscopic appearance of apoptosis?

A
  1. Shrinkage of cell. Organelles are packed into membrane vesicles which bud off (blebs)
  2. Cell fragmentation leading to membrane bound vesicles to bud off (blebs)
  3. Phagocytosis of cell fragments by macrophages and adjacent cells
  4. No leakage of cytosolic components.
39
Q

What are the biochemical changes in microscopic appearance of apoptosis?

A
  1. Expression of charged sugar molecules on outer surface of cell membranes and the vesicles (recognised by macrophages to enhance phagocytosis)
  2. Protein cleavage by caspases
40
Q

How do we activate the initiator caspases?

A

By bringing the caspases close together. ‘By induced proximity’.
Apoptosis = death by a thousand cuts

41
Q

What are the two ways initiator caspases are activated?

A
  1. In response to receptor dimerisation by ligand binding (extrinsic)
  2. Cytochrome C released from the mitochondria (intrinsic)
42
Q

Explain the extrinsic pathway (receptor dimerisation)

A
  1. The receptor has an extracellular ligand binding domain and an intracellular death domain. On binding of ligand (tumour necrosis factor/TNF), there is dimerisation of the death domain of the receptor and the death domain of the death adaptor protein.
  2. This causes the death effector domain of the death adaptor to bind to multiple procaspase 8 proteins so that the procaspases are really close together.
  3. The procaspases then autoproteolyse each other to then form active caspase 8.
  4. Then we get the cascade reaction.
43
Q

What is the ligand needed for the extrinsic pathway?

A

Tumour necrosis factor. It induces the formation of a death inducing signalling complex called DISC.

44
Q

Explain the role of cytochrome C in the intrinsic pathway

A

Cytochrome C is a mitochondrial matrix protein released into cytoplasm when there’s change in mitochondrial membrane permeability.
It is released in response to oxidative stress (as it causes changes in mitochondrial membrane permeability)

45
Q

Explain cytochrome C induced apoptosis

A
  1. APAF-1 protein is in the cytoplasm. It has a cytochrome C binding domain, APAF domain, caspase recruitment domain (CARD). Cytochrome C binds to the cytochrome C domain causes dimerisation of APAF-1 proteins
  2. CARD binds to procaspases 9 and brings them close together to allow them to autoproteolyse each other.
  3. Then the cascade reaction occurs.
46
Q

What does cytochrome C induce?

A

The formation of a death inducing complex

47
Q

How is the release of cytochrome C regulated?

A

It is regulated by bcl-2 family. It has anti-apoptotic and pro-apoptotic members.
They form dimers (homodimers and heterodimers)

48
Q

What are the anti-apoptotic members?

A

bcl-2, bcl-XL and others

49
Q

What are the pro-apoptotic members?

A

Bax, Bad, Bid, others

50
Q

Explain the extrinsic pathway (receptor dimerisation)

A
  1. The receptor has an extracellular ligand binding domain and an intracellular death domain. On binding of ligand (tumour necrosis factor/TNF), there is dimerisation of the death domain of the receptor and the death domain of the death adaptor protein.
  2. This causes the death effector domain of the death adaptor to bind to multiple procaspase 8 proteins so that the procaspases are really close together.
  3. The procaspases then autoproteolyse each other to then form active caspase 8.
  4. Then we get the cascade reaction.
51
Q

What is the ligand needed for the extrinsic pathway?

A

Tumour necrosis factor. It induces the formation of a death inducing signalling complex called DISC.

52
Q

Explain the role of cytochrome C in the intrinsic pathway

A

Cytochrome C is a mitochondrial matrix protein released into cytoplasm when there’s change in mitochondrial membrane permeability.
It is released in response to oxidative stress (as it causes changes in mitochondrial membrane permeability)

53
Q

Explain cytochrome C induced apoptosis

A
  1. APAF-1 protein is in the cytoplasm. It has a cytochrome C binding domain, APAF domain, caspase recruitment domain (CARD). Cytochrome C binds to the cytochrome C domain causes dimerisation of APAF-1 proteins
  2. CARD binds to procaspases 9 and brings them close together to allow them to autoproteolyse each other.
  3. Then the cascade reaction occurs.
54
Q

What does cytochrome C induce?

A

The formation of a death inducing complex

55
Q

How is the release of cytochrome C regulated?

A

It is regulated by bcl-2 family. It has anti-apoptotic and pro-apoptotic members.
They form dimers (homodimers and heterodimers)

56
Q

What are the anti-apoptotic members?

A

bcl-2, bcl-XL and others

57
Q

What are the pro-apoptotic members?

A

Bax, Bad, Bid, others

58
Q

How is the release of cytochrome C regulated?

A

Bax proteins form dimers with each other and then form 6 molecules at the mitochondrial membrane. There’s a pore which allows cytochrome C to be released into the cytosol.

59
Q

What method can you see the 6 molecules of bax?

A

High resolution microscope

60
Q

How is the release of cytochrome C prevented?

A

Blc-2 forms dimers with the 6 molecules of bax and blocks the pore, preventing cytochrome C release into cytosol. As a result, cytochrome C can’t activate procaspases.

61
Q

What happens when a cell is receiving survival signals?

A

Survival signals activate Akt/PKB which phosphorylates Bad, making it inactive so that it can’t bind to bcl-2, hence more bcl-2 is available to block the Bax pore. This prevents cytochrome C release hence prevents apoptosis.

62
Q

What happens when a cell doesn’t receive survival signals?

A

If the cell isn’t receiving survival signals then Akt/PKB isn’t active so can’t phosphorylate Bad, so Bad is active and binds to bcl-2 so less bcl-2 is available to block pore so more cytochrome C is released into cytoplasm which can then activate caspases. Causes apoptosis.

63
Q

What effect does intracellular stress have?

A

Intracellular stress (such as failure to repair DNA) causes transcription (due to p53) of Bax gene and it’s expression. Bax proteins are then inserted into mitochondrial membrane to form more pores to allow cytochrome C to be released into cytosol. This then activates caspases 9 via APAF.

64
Q

What is the most common mutations in cancer?

A

Mutations in p53 gene. This destroys the ability of p53 to induce apoptosis.

When treating cancer, it’s important to know the status of p53.
If it’s not mutated p53, some cancer drugs work by damaging DNA to activate p53 to induce apoptosis.

Clinical Pathology (3 decks)

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