1. Causes Of Cell Injury/death

Question 1

Name different causes of cell injury.

Answer 1

1. Hypoxia
2. Physical agents, e.g. Trauma, temperature extremes, radiation.
3. Chemical agents and drugs, e.g. Alcohol, illicit/therapeutic drugs, high concentrations of oxygen, glucose or salt.
4. Infection
5. Immune mechanisms
6. Dietary insufficiencies/excesses.
7. Genetic abnormalities

Question 2

What is the difference between hypoxia and ischaemia?

Answer 2

Hypoxia = decreased oxygen supply

Ischaemia = decreased blood supply (so decreased oxygen + other nutrients)

Question 3

Name and explain the different causes of hypoxia.

Answer 3

1. Hypoxaemic hypoxia: arterial content of oxygen is low
   
   • reduced inspired pO2 at altitude
   • reduced absorption secondary to lung disease
2. Anaemic hypoxia: decreased ability of haemoglobin to carry oxygen
   
   • anaemia
   • carbon monoxide poisoning
3. Ischaemic hypoxia: interruption to blood supply
   
   • blockage of a vessel
   • heart failure
4. Histiocytic hypoxia: inability to utilise oxygen in cells due to disabled oxidative phosphorylation enzymes
   
   • cyanide poisoning

Question 4

Give examples of cell types that are more or less sensitive to hypoxia.

Answer 4

Neurones are very sensitive - few minutes

Fibroblasts are less sensitive - hours to 1 day

Question 5

In which 2 ways can the immune system damage the body’s cells?

Answer 5

1. Hypersensitivity reactions - host tissue is injured secondary to an overly vigorous immune reaction (e.g. Urticaria)
2. Autoimmune reactions - failure to distinguish self from non-self (e.g. Grave’s disease of thyroid)

Question 6

Which cellular components are most susceptible to injury?

Answer 6

1. Membranes (plasma and intracellular)
2. Mitochondria (oxidative phosphorylation)
3. Nucleus (DNA)
4. Proteins (structural and enzymes)

Question 7

Describe the reversible molecular effects of hypoxia.

Answer 7

• Mitochondria use up O2 supplies so fall in oxidative phosphorylation…
• So decreased ATP levels (to 5-10%):
  
  1. Halting of Na+/K+ ATPase… K+ efflux and influx of Ca2+, Na+ and H2O… cellular swelling, microvilli loss, blebbing, ER swelling, myelin figures.
  2. Increased glycolysis… decreased glycogen and fall in pH… clumping of nuclear chromatin.
  3. Detachment of ribosomes… decreased protein synthesis… lipid deposition.

Question 8

Describe the irreversible molecular effects of prolonged hypoxia.

Answer 8

1. Large calcium cytosolic influx from extracellular environment, mitochondria and ER… activation of :
   - ATPase - decreased ATP
   - phospholipase - decreased phospholipids and disruption of membranes
   - protease - disruption of membrane and cytoskeleton proteins
   - endonuclease - nuclear chromatin damage
2. Enzymes leak out of lysosomes and attack cytoplasmic components.
3. Cell dies, possible as a result of bleb bursting

Question 9

What are free radicals/reactive oxygen species? Name 3 that are of particular biological significance in cells.

Answer 9

• Atoms with single unpaired electron in outer orbit - unstable configuration which reacts with other molecules, often producing further free radicals.
• Hydroxyl (OH.), superoxide (O2-), hydrogen peroxide (H2O2).

Question 10

Name different sources of free radicals.

Answer 10

Endogenous:

• normal metabolic reactions (e.g. Oxidative phosphorylation in MT)
• inflammation (oxidative burst of neutrophils)

Exogenous:

• radiation (splits water to produce hydroxyl)
• drugs and chemicals (e.g. Metabolism of paracetamol or carbon tetrachloride by P450 in liver)
• contact with unbound metals in body: iron (Fenton reaction) and copper

Question 11

Name 2 diseases in which free radical damage occurs as a result of contact with unbound metals in the body.

Answer 11

Haemachromatosis (iron excess)

Wilson’s disease (copper excess)

Question 12

How do free radicals injure cells?

Answer 12

• Cause lipid peroxidation of cell membranes… generation of further free radicals (= autocatalytic chain reaction).
• Oxidise proteins, carbohydrates and DNA… causes denaturation, breakage or cross-linking… mutagenic and so carcinogenic,

Question 13

As a result of what are free radicals usually produced?

Answer 13

1. Chemical and radiation injury
2. Ischaemia-reperfusion injury
3. Cellular ageing
4. High oxygen concentration

Question 14

Which defence system protects against free radicals and what does this consist of?

Answer 14

Anti-oxidant system:

1. Enzymes
   
   • Superoxide dismutase catalyses reaction from hydroxyl to hydrogen peroxide (significantly less toxic).
   • Catalases and peroxidases complete process of free radical removal (H2O2 to O2 + H2O).
2. Free radical scavengers - neutralise free radicals: vitamins A, C and E.
3. Storage proteins - sequester transition metals in extracellular matrix (e.g. Transferrin and ceruloplasmin sequester iron and copper).

Question 15

Name a defence pathway that protects the cell against several types of injury.

Answer 15

Heat shock proteins (Hsp), e.g. Ubiquitin, which guide mis-folded proteins through refolding process.

Question 16

Give an example of how a chemical agent causes cell injury.

Answer 16

Cyanide binds to mitochondrial cytochrome oxidase and blocks oxidative phosphorylation.

Question 17

What is ischaemia-reperfusion injury? How does this damage cells?

Answer 17

Blood flow returning to a tissue subjected to ischaemia but not yet necrotic. Effects may be worse than is blood flow was not restored.

1. Increased production of oxygen free radicals with reoxygenation.
2. Increased number of neutrophils following reinstatement of blood supply resulting in more inflammation and increased tissue injury.
3. Delivery of complement proteins and activation of the complement pathway.