Cell Damage and Cell Death

Question 1

What are the genetic causes/mechanisms of cell death

Answer 1

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)

Question 2

What are the inflammatory causes/mech of cell death

Answer 2

Trauma
Thrombo-embolism
Atherosclerosis
Vasculitis

Question 3

What are the physical causes/mech of cell death

Answer 3

Irradiation
Heat
Cold
Barotrauma

Question 4

What are the chemical causes/mech of cell death

Answer 4

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

Question 5

What are the causes/mech of infection on cell death

Answer 5

Toxic agents 
Competition for nutrients 
Intracellular replication 
  - viruses/mycobacteria provoking 
    an immune response

Question 6

What are the causes/mech of traumatic damage on cell damage

Answer 6

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

Question 7

What is barotrauma

Answer 7

Increased air/water pressure

Question 8

What is metamorphosis

Answer 8

Process by which an animal physically develops after birth or hatching

Question 9

What is necrosis and when does it occur

Answer 9

Cell injury which results in the premature death of cells in living tissue by autolysis

Occurs after stresses such as ischemia, trauma, chemical injury

Question 10

What is apoptosis and what is it’s purpose

Answer 10

Programmed cell death.

Eliminates unwanted host cells by activation of a co-ordinated, internally programmed series of events effected by a dedicated set of gene products

Question 11

What is autophagic cell death

Answer 11

Degradation of normal proteins in cellular remodeling (metamorphosis, aging + differentiation)

Digestion/removal of abnormal proteins ( if not = accumulate following toxin exposure, cancer, or disease)

Question 12

Causes of necrosis

Answer 12

Usually caused by a lack of blood supply to cells/tissues
Injury
Infection
Cancer
Infarction 
Inflammation

Question 13

Relationship between pH, pO2 and distance from vessel

Answer 13

As distance from vessel increases, the pH decreases and pO2 decreases (0 after around 200mm)

Question 14

Describe 7 properties of necrosis

Answer 14

Whole of group of cells affected

Result of an injurious agent or event

Reversible events proceed irreversible

Energy deprivation causes changes (No ATP as no O2)
Cells swell due to influx of water (ATP required for ion transport)

Haphazard destruction of organelles + nuclear material by enzymes from ruptured lysosomes

Cellular debris stims inflammatory response

Question 15

Describe nuclear changes in necrosis

Answer 15

Chromatin condensation/shrinkage
Fragmentation of nucleus
Dissolution of chromatin by DNAse

Question 16

Describe the cytoplasmic changes in necrosis

Answer 16

Opacification: denaturation of proteins with aggregation.

Complete digestion of cells by enzymes causing cell to liquify (liquefactive necrosis).

Question 17

What are the biochemical changes in necrosis

Answer 17

Release of enzymes such as creatine kinase or lactate dehydrogenase
Release of proteins such as myoglobin

Question 18

Why are biochemical changes useful

Answer 18

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

Question 19

What is an astrocytoma - describe it’s spread

Answer 19

Brain tumour in cerebrum glial cells = astroycytes

Doesn’t spread out brain/spinal cord + does not usually effect other organs

Question 20

What is the function of necrosis and what does a failure in this lead to

Answer 20

Removes damaged cells from an organism

Failure = may lead to chronic inflammation

Question 21

Apoptosis - define and list what it’s involved in

Answer 21

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

Involved in:-
Embryogenesis
Metamorphosis
Normal tissue turnover
Endocrine-dependent tissue atrophy
A variety of pathological conditions

Question 22

Give 8 examples of apoptosis

Answer 22

Cell death in embryonic hand to form individual fingers

Apoptosis induced by growth factor deprivation

DNA damage-mediated apoptosis

Cell death in tumours causing regression

Cell death in viral diseases

Cell death induced by cytotoxic T cells

Death of neutrophils during an acute inflammatory response

Death of immune cells after depletion of CKs + autoreactive T cells in thymus

Question 23

Survival due to

Answer 23

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

Question 24

Apoptosis due to

Answer 24

Death domain ligands
DNA damaging agents
Lack of growth factors
Disruption of c-c and/or c-m contacts

Question 25

Describe intrinsic apoptosis

Answer 25

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

Question 26

Describe extrinsic apoptosis

Answer 26

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

Question 27

What are caspases

Answer 27

Cysteine Aspartate-specific Proteases Role = initiation of apoptosis

Question 28

Describe the intracellular proteolytic cascade

Answer 28

Active caspase X activates PC Y Cleaves sites close to amine/carboxyl terminal domain 2 parts now form a dimer AC Y formed

Question 29

Caspase activation leads to what changes in cell

Answer 29

``` Morphological changes of cell: Shrinkage Chromatin condensation DNA fragmentation Plasma membrane blebbing ```

Question 30

Describe the features of apoptosis

Answer 30

Single or few cells selected. Programmed cell death. Irreversible once initiated. Events are energy driven. Cells shrink as the cytoskeleton is disassembled. Orderly packaging of organelles + nuclear fragments in membrane bound vesicles. New molecules expressed on vesicle membranes stim phagocytosis = no inflammatory response

Question 31

Describe the nuclear changes in apoptosis

Answer 31

Nuclear chromatin condenses on nuclear membrane | DNA cleavage

Question 32

Describe the cytoplasmic changes in apoptosis

Answer 32

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

Question 33

Describe the biochemical changes in apoptosis

Answer 33

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

Question 34

Describe and explain the role of TNF

Answer 34

TNF = tumour necrosis factor FADD = fas-associated protein w/death domain = FADD = adaptor protein, Bridges members of TNF PC-8 activated = autoproteolysis TNF induces the formation of a death-inducing signalling complex = DISC

Question 35

What is cytochrome C

Answer 35

Mitochondrial matrix protein Released in response to oxidative stress by “permeability transition” Any inducers of the permeability transition also eventually induce apoptosis

Question 36

Describe and explain the role of C-c

Answer 36

C-c binding site for APAF domain Caspase recruitment domain binds protease domain (PC-9) Cytochrome c induces the formation of a death-inducing complex

Question 37

C-c release regulation

Answer 37

If cells receiving correct survival signals then PKB responds = then bad is phosphorylated thus inactive When active = Bad outcompetes bcl-2 for bax binding

Question 38

Intracellular stress leads to...

Answer 38

IS - transcription (e.g. by p53) There is membrane insertion of bax Death due to APAF/caspase-9

Question 39

Describe the link between p53/apoptosis and cancer

Answer 39

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