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2 - Cellular Pathology > 2 - CELL DAMAGE AND CELL DEATH > Flashcards

2 - CELL DAMAGE AND CELL DEATH Flashcards

1
Q

Causes and mechanisms of cell damage / death - Genetic 5

A
  • Abnormal number chromosomes (aneuploidy)
  • Abnormal chromosomes (deletions/translocations)
  • Increased fragility (Fanconi’s anaemia)
  • Failure of repair (Xeroderma pigmentosa)
  • Inborn errors (Storage disorders ie. Tay Sachs disease)
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2
Q

Causes and mechanisms of cell damage / death - Inflammation 4

A
  • Trauma
  • Thrombo-embolism
  • Atherosclerosis
  • Vasculitis
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3
Q

Causes and mechanisms of cell damage / death - Physical 4

A
  • Irradiation
  • Heat
  • Cold
  • Barotrauma
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4
Q

Causes and mechanisms of cell damage / death - Traumatic damage 3

A
  • Interruption of blood supply
  • Direct rupture of cells
  • Entry of foreign agents
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5
Q

Causes and mechanisms of cell damage / death - Infection 3

A
  • Toxic agents
  • Competition for nutrients
  • Intracellular replication (viruses/mycobacteria provoking an immune response)
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6
Q

Causes and mechanisms of cell damage / death - Chemical 3

A
  • Acids/corrosives
  • Specific actions e.g. enzymes
  • Interference with metabolism e.g. alcohol
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7
Q

Cell death is caused by three basic mechanisms 3

A

Necrosis: Most common cause of cell death. Occurs after stresses such as ischemia (lack of O2) , trauma, chemical injury. ‘Death by accident’.

Apoptosis: Programmed cell death. Designed to eliminate unwanted host cells through activation of a co-ordinated, internally programmed series of events effected by a dedicated set of gene products. ‘Death by design’.

Autophagic cell death: Autophagy is responsible for the degradation of normal proteins involved in cellular remodelling found during metamorphosis, aging and differentiation as well as for the digestion and removal of abnormal proteins that would otherwise accumulate following toxin exposure, cancer, or disease. An example is the death of breast cancer cells induced by Tamoxifen.

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8
Q

Define Necrosis 1

A

Necrosis: Most common cause of cell death. Occurs after stresses such as ischemia (lack of O2) , trauma, chemical injury. ‘Death by accident’.

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9
Q

Define Apoptosis 1

A

Apoptosis: Programmed cell death. Designed to eliminate unwanted host cells through activation of a co-ordinated, internally programmed series of events effected by a dedicated set of gene products. ‘Death by design’.

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10
Q

Define Autophagic cell death 1

A

Autophagic cell death: Autophagy is responsible for the degradation of normal proteins involved in cellular remodelling found during metamorphosis, aging and differentiation as well as for the digestion and removal of abnormal proteins that would otherwise accumulate following toxin exposure, cancer, or disease. An example is the death of breast cancer cells induced by Tamoxifen.

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11
Q

Process of Necrosis 7

A
  1. Whole groups of cells are affected.
  2. Result of an injurious agent or event.
  3. Reversible events proceed irreversible.
  4. Energy deprivation causes changes. (e.g. cells unable to produce ATP because of oxygen deprivation)
  5. Cells swell due to influx of water (ATP is required for ion pumps to work).
  6. Haphazard destruction of organelles and nuclear material by enzymes from ruptured lysosomes. Affects near by healthy cells, sugars, proteins etc.
  7. Cellular debris stimulates an inflammatory cell response
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12
Q

Causes of Necrosis 5

A

Usually caused by lack of blood supply (so no ATP or O2) to cells or tissues, e.g.

  1. Injury (Car crash)
  2. Infection (Competition for nutrients involved)
  3. Cancer (Cancer can lead to necrosis –> as the cells expand, it compresses neighbouring blood vessels –> restriction of blood flow)
  4. Infarction
  5. Inflammation (Tissues expand so this restricts blood vessels)
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13
Q

pH and po2 at various distances (µm) from a blood vessel 2

A

It shows that pH and oxygen levels are both very high when you are closer to the blood vessels. They both decrease quite rapidly.

As you move along a blood vessel pH and pO2 decrease.

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14
Q

Microscopic Appearance of Necrosis 3

A
  1. Nuclear changes
  2. Cytoplasmic changes
  3. Biochemical changes
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15
Q

Microscopic Appearance of Necrosis - Nuclear Changes 3

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

Microscopic Appearance of Necrosis - Cytoplasmic Changes 2

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

Microscopic Appearance of Necrosis - Biochemical Changes 2

A
  1. Release of enzymes such as creatine kinase or lactate dehydrogenase
  2. Release of proteins such as myoglobin

These biochemical changes are useful in the clinic to measure the extent of tissue damage.

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18
Q

What is a Astrocytoma 4

A

An example of necrotic tissue, it is a cancerous tissue

Astrocytoma count for 60% of brain tumours

Tumour is erasing the normal histology shape or brain cells.

The cancer cells are erasing nearby tissue  the nearby tissues undergo necrosis  the necrotic tissue is darker.

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19
Q

Normal and Necrotic Kidney 5

A
  • Glomurli, E and T staining in the kidney. Clearly see cell DNA nucleus.
  • What we can see in the necrotic glomeruli the DNA is totally degraded so lack of DNA staining. Known as ghost cells they were there but nothing inside the cell compartment.
  • An example of necrotic glomeruli
  • The DNA is totally degraded
  • Called ghost cells –> it looks like the cell is there but if you look closely, there is nothing inside
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20
Q

What is a ghost cells 1

A

A ghost cells looks like the cell is there but if you look closely, there is nothing inside

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21
Q

Functions of Necrosis 2

A
  1. Removes damaged cells from an organism
  2. Failure to do so may lead to chronic inflammation.
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22
Q

Is necrosis a reversible process 1

A

Most of the time yes

We can restore the function by providing cells with ATP.

Therefore, necrosis is a reversible process.

However, if the amount of water entering the cell is massive, you reach the point of no return  the swelling is irreversible.

The organelles within, such as the nucleus, mitochondria and lysosomes swell as well.

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23
Q

Process of Apoptosis 7

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 membranes stimulate phagocytosis, no inflammatory response.
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24
Q

Functions of Apoptosis 6

A
  1. Selective process for the deletion of superfluous (not required by organism anymore), infected or transformed cells. Involved in:
  2. Embryogenesis
  3. Metamorphosis
  4. Normal tissue turnover
  5. Endocrine-dependent tissue atrophy
  6. A variety of pathological conditions
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25
Q

Examples of apoptosis 10

A
  1. Cell death in embryonic hand to form individual fingers.
  2. Apoptosis helps eliminate the tail during the metamorphosis of a tadpole into a frog.
  3. Apoptotic Cell Death during The Development of Mouse Paws
  4. Apoptosis induced by growth factor deprivation (neuronal death from lack of NGF).
  5. DNA damage-mediated apoptosis. If DNA is damaged due to radiation or chemo therapeutic agents, p53 (tumour suppressor gene product) accumulates. This arrests the cell cycle enabling the cell repair the damage. If repair process fails, p53 triggers apoptosis.
  6. Cell death in tumours causing regression.
  7. Cell death in viral diseases (i.e. viral hepatitis).
  8. Cell death induced by cytotoxic T cells (i.e. Cellular immune rejection or graft vs. host disease).
  9. Death of neutrophils during an acute inflammatory response.
  10. Death of immune cells( both T and B lymphocytes) after depletion of cytokines as well of death of autoreactive T cells in the developing thymus.
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26
Q

Examples of Apoptosis - Apoptosis helps eliminate the tail during the metamorphosis of a tadpole into a frog 1

A

Tail undergoes apoptosis, allows the organism to be fitter than the tadpole as it can leave pond which is oversaturated with tadpoles, better for competition.

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27
Q

Examples of Apoptosis - Apoptotic Cell Death during The Development of Mouse Paws 3

A

cosmetic issues

during dev if apoptosis goes faulty it is prevalent, can tell.

during evolution webbed has gone.

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28
Q

Factors influencing the balance of life and death at the cellular level

A

.

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29
Q

What tells cells they will survive 2

A

If they are in the right environment, with the right growth factors present and the right cytokines present.

The cell-cell/cell-matrix contacts are very important.

The signals that tell them to undergo apoptosis are the opposite

30
Q

Two types of apoptosis 2

A
  1. Intrinsic
  2. Extrinsic
31
Q

Types of apoptosis - Intrinsic 5

A
    • DNA damage – p53-dependent pathway
    • Interruption of the cell cycle
    • Inhibition of protein synthesis
    • Viral Infection
    • Change in redox state
32
Q

Types of apoptosis - Extrinsic 3

A
    • Withdrawal of growth factors (e.g. IL-3)
    • Extracellular signals (e.g. TNF)
    • T cell or NK (Natural Killer) (e.g. Granzyme).
33
Q

What are caspases 1

A

Caspases are Cysteine Proteases that play a central role in the initiation of apoptosis.

34
Q

Where can caspases be found 1

A

Present in cells as synth as precursors

35
Q

How are most proteases synthesised 1

A

Most proteases are synthesised as inactive precursors requiring activation (usually partial digestion by another protease).

36
Q

What is apoptosis mediated by 1

A

Apoptosis is mediated by an intracellular proteolytic cascade

37
Q

Apoptosis - intracellular proteolytic cascade 7

A
  1. Procaspase can be activated with caspase.
  2. Caspace x can be expressed in cells.
  3. In active procapase y , active caspace x cleaves at both cleavage sites.
  4. Procaspase Y is inactive but is activated and cleaved by active caspase X.
  5. This cleaves specifically to form a large and small subunit which make a dimer.
  6. Now you have active caspase Y.
  7. Caspase X is also initially expressed as an inactive form in cells.
38
Q

Caspase Cascade 5

A
  • Caspase activation leads to characteristic morphological changes of the cell such as shrinkage, chromatin condensation, DNA fragmentation and plasma membrane blebbing.
  • When you trigger apoptosis, you have an active initiator caspase (usually 8/9).
  • The active form of this caspase will activate other caspases and as a result you start to cleave cytosolic proteins that contain cysteine-aspartate residues.
  • The actin cytoskeleton starts to breakdown and the cell starts to collapse.
  • This caspase can then activate many effector caspases (1,3,6,7) which leads to a massive amplification of proteolysis. Eventually, you also end up cleaving the nuclear lamin (this is a protein which is required for the nuclear envelope).
39
Q

What does caspase activation lead to in apoptosis 1

A

Caspase activation leads to characteristic morphological changes of the cell such as shrinkage, chromatin condensation, DNA fragmentation and plasma membrane blebbing.

40
Q

Morphological features of apoptosis 3

A

The healthy cells will receive a stimulus that triggers apoptosis.

The cells become rounded and start to collapse mainly due to the actin cytoskeleton being degraded.

If you follow the cells over time, they would detach from the substrate and would be seen floating.

Start to see the formation of blebs.

Inside blebs, there are mitochondria, lysosomes, etc.

Eventually, these vesicles bud off the cells and are coated with sugars.

This is a signal for them to be engulfed by nearby macrophages via phagocytosis.

41
Q

What are some ways to visualise cell death 2

A

TEM transmission electron micrography

SEM scanning electron micrography.

42
Q

How can you differentiate different kinds of cell death based on DNA fragmentation 4

A
  • You would take a sample of purified DNA from the cell in question and run it through gel electrophoresis.
  • Cells that are normal will have their DNA at one specific band.
  • Cells that are apoptosing will have multiple bands of decreasing levels at certain intervals.
  • While cells that are necrosing will have continuously decreasing DNA.
43
Q
A
44
Q

In DNA fragmentation why doesn’t the genomic DNA run on the electrophoresis gel 1

A

The genomic DNA of a normal cell has a high molecular weight, so it does not run on the gel.

45
Q

Describe how apoptosis looks in DNA fragmentation on the electrophoresis gel 3

A
  • Cell undergoing apoptosis show a very clear ladder structure.
  • Each one of the fragments signifies 150 base pairs wrapped around the nucleosome.
  • In apoptotic cells, the nucleosomes are intact as well as the DNA surrounding them.
46
Q

Describe how necrosis looks in DNA fragmentation on the electrophoresis gel 3

A

In cells undergoing necrosis, the fragmentation of DNA is random.

This is because the cells don’t have nucleosomes.

In necrotic cells, the enzymes that are released by the cell cleave all the nucleosomes and so the DNA is naked and broken randomly.

47
Q

Microscopic Appearance of Apoptosis 3

A

Nuclear Changes

Cytoplasmic Changes

Biochemical changes

48
Q

Microscopic Appearance of Apoptosis - Nuclear Changes 2

A

Nuclear chromatin condenses on nuclear membrane.

DNA cleavage.

49
Q

Microscopic Appearance of Apoptosis - Cytoplasmic Changes 4

A

Shrinkage of cell. Organelles packaged into membrane vesicles.

Cell fragmentation. Membrane bound vesicles bud off.

Phagocytosis of cell fragments by macrophage and adjacent cell.

No leakage of cytosolic components.

50
Q

Microscopic Appearance of Apoptosis - Biochemical changes 2

A

Expression of charged sugar molecules on outer surface of cell membranes (recognised by macrophages to enhance phagocytosis)

Protein cleavage by proteases, caspases

51
Q

Caspase Cascade - Substrates for activated caspases 8

A

Substrates for activated caspases

The list below shows the substrate and the function is blocks

  • Lamin A and B  Nuclear envelope breakdown
  • PARP  DNA repair
  • DNA-PK  DNA repair
  • Topoisomerase II  DNA replication
  • Raf-1  Signalling
  • Akt/PKB  Cell survival
  • STAT1  Signalling
  • eIF4  Translation
52
Q

How do we activate the initiator caspases

A

By induced proximity

53
Q

Name 2 examples of how we activate initiator caspaces 2

A
  1. In response to receptor dimerization upon ligand binding OR
  2. Cytochrome C release from the mitochondria
54
Q

Key components of the Ligand-induced dimerisation 4

A

In the extrinsic pathway:

Receptor is on the membrane.

Inside the cell there is the DEATH DOMAIN and outside the cell there is the LIGAND BINDING DOMAIN.

The RECEPTOR recruits an adaptor protein which makes dimers with the death domain however, it also brings inactive procaspase-8 with it.

The PROCASPASE-8, with a death effector domain and a protease domain

55
Q

What happens when the key components of the ligand-induced dimerisation come together 1

A

When they all bind together, the PROCASPASE-8’s will all be in close proximity, which will cause their autoproteolysis, activating them.

All including

  • the RECEPTOR, with a ligand binding domain and a death domain
  • the DEATH ADAPTOR, with a death domain and a death effector domain
  • the PROCASPASE-8, with a death effector domain and a protease domain
56
Q

What does TNF (Tumor necrosis factor) induce the formation of 1

A

TNF induces the formation of a death-inducing signalling complex = DISC (EXTRINSIC PATHWAY)

57
Q

DISC: Extrinsic pathway - Steps 5

A
  1. These cells receive death ligand, in this case TNF.
  2. TNF brings together several receptors for itself which come together on the death adaptor protein.
  3. The death adaptor protein brings a lot of Procaspase-8 in close proximity.
  4. As a result of the close proximity, there is autoproteolysis of the procaspase 8.
  5. The outcome of this is that you have ACTIVE procaspase-8
58
Q

What is Cytochome C 3

A

Mitochondrial matrix protein

Released in response to oxidative stress by a “permeability transition”

Any inducers of the permeability transition also eventually induce apoptosis.

59
Q

When is Cytochrome C released 1

A

Released in response to oxidative stress by a “permeability transition”

60
Q

Key components of the Cytochrome c-induced apoptosis 5

A
  • Cytochrome C has binding sites on this molecule called APAF.
  • APAF-1 has a domain (CARD) which can bind and recruit caspases (in this case it is caspase 9).
  • Procaspase-9, with a caspase recruitment domain (CARD) and a protease domain
  • A few cytochrome C molecules can bring together a few APAF molecules which in turn brings together a few inactive Procaspase-9 molecules.
  • Due to the close proximity, you get autoproteolysis, and the procaspase-9 becomes activated.
61
Q

Name an intrinsic and extrinsic pathway that can lead to apoptosis 2

A

Intrinsic

Cytochrome c-induced apoptosis

Extrinsic:

Ligand-induced dimerisation

TNF induces the formation of a death-inducing signalling complex = DISC

62
Q

How is the release of Cytochrome C regulated? 3

A

There are two types of units:
ANTI-APOPTOTIC:
- bcl-2
- bcl-XL

PRO-APOPTOTIC:

  • Bax
  • Bad
  • Bid

Can form homodimers within themselves or hetero with another family member. There is a balance between life and death depending on which family members from homo/heterodimers

63
Q

Name some anti-apoptotics involved in the Cytochrome C regulation 2

A
  1. bcl-2
  2. bcl-XL
64
Q

Name some pro-apoptotics involved in the Cytochrome C regulation 3

A
  1. Bax
  2. Bad
  3. Bid
65
Q

How is the release of Cytochrome C regulated - ANTI-APOPTOTIC 4

A

Bcl-2 is a member of a multi-gene family in mammals.

The bcl-2 family members form dimers.
It regulates the release of cytochrome c form mitochondria.

If one or more of the dimer units is anti-apoptotic, they promote life.

With the anti-apoptotic bcl-2 units, they block that channel to avoid its release, but the pro-apoptotic ones dimerise and remove them, allowing its release.

66
Q

How is the release of Cytochrome C regulated - PRO-APOPTOTIC 3

A

If both dimer units are pro-apoptotic, then they promote death.

Bax proteins can congregate to form a channel in the mitochondrial membrane, which would allow the cytochrome-C out.

With the anti-apoptotic bcl-2 units, they block that channel to avoid its release, but the pro-apoptotic ones dimerise and remove them, allowing its release.

67
Q

How is the release of Cytochrome C regulated? A4 SHEET

A

A4 SHEET

68
Q

Where do the most common mutations in cancer take place 1

A

Mutations in the p53 gene are the most common mutations in cancer.

69
Q

p53 and cancer and apoptosis 2

A

Some mutations destroy the ability of p53 to induce Apoptosis.

p53 is used in anti-cancer drugs as if p53 is active it can reduce DNA damage and induce apoptosis of tumours.

70
Q

Apoptosis vs Necrosis - table

A

Apoptosis vs Necrosis - table

2 - Cellular Pathology (24 decks)

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