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SEM 4:Cellular Pathology > Cell Death and Cell Damage > Flashcards

Cell Death and Cell Damage Flashcards

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1
Q

What are the causes and mechanisms of cell damage/death?

A
  • Genetics: Abnormal no. chromosomes and chromosomes, increased fragility, failure of repair, inborn errors are all inherited diseases that can lead to cell death
  • Inflammation: trauma, thrombo-embolism, atherosclerosis, vasculitis - inflammation of blood vessels
  • Physical: irradiation, heat, cold, barotrauma are physical causes of cell death
  • Traumatic Damage: Interruption of blood supply, direct rupture of cells, entry of foreign agents for example stabbing
  • Infection: Toxic agents, competition for nutrients, intracellular replication
  • Chemical: acids/corrosives, specific actions, interference with metabolism
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2
Q

When does necrosis occur?

A

The most common cause of cell death. This occurs after stresses such as ischemia, trauma, chemical injury.

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3
Q

What are the three basic mechanisms for cell death?

A

Necrosis, Apoptosis, and Autophagic cell death

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4
Q

What is apoptosis?

A

Programmed cell death.

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5
Q

Purpose of apoptosis

A

To eliminate unwanted host cells through activation of co-ordinated, internally programmed series of effects effected by a dedicated set of gene products.

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6
Q

What is autophagic cell death?

A

Autophagy is responsible for the degradation of normal proteins involved in cellular remodelling found during metamorphosis, ageing and differentiation as well as for the digestion and removal of abnormal proteins that would otherwise accumulate following toxin exposure, cancer or disease.

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7
Q

Example of autophagic cell death

A

Death of breast cancer cells induced by tamoxifen

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8
Q

Causes of necrosis

A
  • Usually caused by lack of blood supply to cells or tissues e.g.
  • Injury
  • Infection
  • Cancer
  • Infarction
  • Inflammation
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9
Q

How does injury cause necrosis?

A

Injury causes the loss of blood supply to the tissues so there is no oxygen, no ATP and no energy. Therefore causes necrosis.

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10
Q

How does infection cause necrosis?

A

Bacteria competes for oxygen meaning there is no oxygen, no ATP, no energy which causes necrosis.

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11
Q

How does cancer cause necrosis?

A

Cancer causes the expansion of nearby blood vessels so competition for oxygen, no ATP, no energy causes necrosis.

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12
Q

How does infarction cause necrosis?

A

It prevents blood flow to specific regions, no oxygen, no ATP so no energy which causes necrosis.

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13
Q

How does inflammation cause necrosis?

A

Restriction of blood flow, so no oxygen, no ATP so no energy which causes necrosis.

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14
Q

How does the distance of vessels from oxygen affect the chance of necrosis?

A

When there is no distance, there are higher levels of oxygen so higher pH, or more neutral. When there is a further distance, there is lower levels of oxygen so lower pH and lower oxygen.

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15
Q

Effects of necrosis

A
  1. Whole group 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
  7. Cellular debris stimulates an inflammatory cell response
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16
Q

What is the effect of necrosis on cells?

A

The cell isn’t receiving oxygen so there is no energy. The ion channels stop working so there is no electrolyte balance. There is an increase in water into cells which causes lysis. The lysis can cause reversible swelling but if the swelling is too large, it is irreversible and causes disintegration of the cell, nucleus, and breakdown of lysosomes.

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17
Q

How does the breakdown of lysosomes affect cells?

A

Their breakdown releases enzymes that affect nearby healthy cells. This will stimulate an inflammatory cell response.

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18
Q

Describe the microscopic appearance of necrosis

A
  1. Chromatin condensation/shrinkage
  2. Fragmentation of nucleus
  3. Dissolution of the chromatin by DNAse (Breakdown DNA by DNAse I which randomly cleaves).
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19
Q

Cytoplasmic changes of necrosis

A

Cytoplasm becomes opaque as there is a denaturation of proteins with aggregation. The complete digestion of cells by enzymes causes cells to liquify (liquefactive necrosis).

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20
Q

Biochemical changes of necrosis

A
  • Release of enzymes such as creatine kinase or lactate dehydrogenase
  • Release of proteins such as myoglobin
21
Q

What are the biochemical changes of necrosis important for?

A

Useful in the clinic to measure the extent of tissue damage

22
Q

Astrocytoma of the brain

A

Caused by cancer cells will erase nearby tissues causing necrosis. The brain tissue is darker as a denaturation of proteins. It is highly aggressive.

23
Q

How to identify necrosis in tissues?

A

Necrotic tissue has an opaque appearance and the DNA has degraded so no nuclear staining -> appear as Ghost cells

24
Q

What does necrosis do?

A

It removes damaged cells from an organism and failure to remove may lead to chronic inflammation.

25
Q

Function of apoptosis

A

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

  • Embryogenesis
  • Metamorphosis
  • Normal tissue turnover
  • Endocrine-dependent tissue atrophy
  • A variety of pathological conditions
26
Q

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.
  4. Cell death in tumours causing regression - cells detect that they are becoming cancerous.
  5. Cell death in viral diseases (i.e. viral hepatitis)
  6. Cell death induced by cytotoxic T cells (i.e. cellular immune rejection or graft vs. host disease)
  7. Death of neutrophils during an acute inflammatory response.
  8. Death of immune cells after depletion of cytokines as well as the death of autoreactive T cells in the developing thymus.
27
Q

Why is apoptosis important during development?

A

Apoptosis helps eliminate the tail during the metamorphosis of a tadpole into a frog. Or for example in mouse paws. It is good during development to allow animals to be fitter.

28
Q

Factors that promote survival and apoptosis

A

Survival:

  • Cell-cell and/or cell-matrix contacts
  • Growth factors
  • Cytokines

Apoptosis:

  • Death domain ligands
  • DNA damaging agents
  • Lack of growth factors
  • Disruption of cell-cell and/or cell-matrix contacts
29
Q

What are the two types of apoptosis?

A

Intrinsic and Extrinsic apoptosis

30
Q

Intrinsic apoptosis

A

Triggered from within the cells

  • DNA damage - p53 dependent pathway
  • Interruption of the cell cycle
  • Inhibition of proteins synthesis
  • Viral infection
  • Change in redox state
31
Q

Extrinsic apoptosis

A

Triggered by extracellular factors

  • Withdrawal of growth factors (e.g. IL-3)
  • Extracellular signals (e.g. TNF)
  • T cell or NK (natural killer) e.g. granzyme
32
Q

What are caspases?

A

Cysteine Aspartate-specific proteases

33
Q

Function of caspases

A

Cysteine proteases that play a central role in the initiation of apoptosis. They cleave other proteins with cysteine aspartate. Most proteases are synthesized as inactive precursors requiring activation (usually partial digestion by another protease).

34
Q

What is the intracellular proteolytic cascade that mediates apoptosis?

A
  1. An inactive procaspase Y that is activated by an active caspase X.
  2. This clips the sides, near the COOH terminal and the NH2, the prodomain off and leaves the large and small subunit.
  3. This leaves an active caspase Y.
  4. This active caspase (8 or 9) activates the first kinase by cleaving the other members of the caspase molecules but the first caspase Y.
35
Q

What does the caspase cascade cause?

A
  • Actin filaments and microfilaments cleaved causing the loss of the cytoskeleton.
  • The nuclear envelope is broken down.
  • This leads to characteristic morphological changes of the cell such as shrinkage, chromatin condensation, DNA fragmentation and plasma membrane blebbing.
36
Q

Why are apoptotic cells phagocytosed?

A

Buds on cells are recognized by phagocytes

37
Q

Explain apoptotic cell DNA fragments

A

Ordered progression of breakdown

38
Q

Summarise 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 membranes stimulate phagocytosis, no inflammatory response
39
Q

Two mechanisms that activate the initiator caspases

A

By induced proximity e.g. in response to receptor dimerization upon ligand binding or Cytochrome C release from the mitochondria

40
Q

Ligand-induced dimerization - Extrinsic Pathway

A
  1. The receptor has two domains: ligand binding and death domain.
  2. The death-domain binds to a death adaptor that binds to a protease domain (procaspase-8).
    This is induced by tumour necrosis factor (TNF) - which causes the formation of a death-inducing signalling complex (DISC). These bind to TNFR. Which bind to FAS-associated protein with Death Domain (FADD). This activates procaspase 8. This is autoproteolytic causing the degradation of the whole thing.
41
Q

Why is autoproteolysis important in ligand-induced dimerization?

A

This produces more active procaspase-8 leading to degradation of the whole thing.

42
Q

What is cytochrome C?

A
  • Mitochondrial matrix protein: released from the mitochondria
  • Change in the mitochondria membrane results in cell death
  • Known for many years to be released in response to oxidative stress by a “permeability transition”
  • Any inducers of the permeability transition also eventually induce apoptosis.
43
Q

Cytochrome-c induced apoptosis - Intrinisic Pathway

A

Occurs only in the mitochondria.

  1. Cytochrome C binds to the binding site on the Apoptotic Protease Activating Factor-1 (APAF-1).
  2. There is two APAF-1: one on the protease domain and CARD. These are brought closer together and cleave each other.
  3. This binds to the protease domain via the caspase recruitment domain (CARD) and onto procaspase-9.
  4. The active procaspase-9 autoproteolysises and triggers apoptosis.
44
Q

Which factors regulate the release of cytochrome C?

A

bcl-2 and Bad.
These form dimers which either favour life or death.
bcl-2 x bcl-2: life
bcl-2 x Bad: life
Bad x Bad: death
The factor will bind to the receptor on the outer mitochondrial membrane side and this will block the release of cytochrome C.

45
Q

Anti-apoptotic proteins

A

bcl-2, bcl-XL, others

46
Q

Pro-apoptotic proteins

A

Bax, Bad, Bid, others

47
Q

p53 and apoptosis

A

Mutations in the p53 gene are the most common mutations in cancer. Some mutations destroy the ability of p53 to induce apoptosis.

48
Q

Importance of survival factors

A

Withdrawal of survival factors will mean that cytochrome C is able to pass through the receptor. This will activate a death signal which will cause apoptosis.

SEM 4:Cellular Pathology (13 decks)

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