Week 1 - Cell Injury

Question 1

List the causes of cell injury and cell death.

Answer 1

1. Hypoxia
2. Physical agents, e.g. trauma, heat, cold, radiation
3. Chemical agents and drugs, e.g. poisons, alcohol, therapeutic drugs
4. Microorganisms: viruses, bacteria, fungi and other parasites
5. Immune mechanisms (hypersensitivity reactions or autoimmune reactions)
6. Dietary insufficiency and dietary excess
7. Genetic abnormalities, e.g. inborn errors of metabolism

Question 2

Define ischaemia.

Answer 2

Loss of blood supply due to reduced arterial supply (e.g. obstruction of an artery, hypotension) or reduced venous drainage

Question 3

Outline the causes of hypoxia.

Answer 3

1. Hypoxaemic: Arterial content of oxygen is low, e.g. reduced inspired pO2 at altitude
2. Anaemic: Decreased ability of haemoglobin to carry oxygen, e.g. anaemia, carbon monoxide poisoning
3. Ischaemic: Interruption to blood supply, e.g. blockage of a vessel, heart failure
4. Histocytic: Inability to use oxygen in cells due to disabled oxidative phosphorylation enzymes, e.g. cyanide poisoning

Question 4

List the main targets of cell injury.

Answer 4

1. Cell membranes - Plays an essential role in homeostasis and the organellar membranes which compartmentalize organelles such as lysosomes
2. Nucleus - contains the genetic material of the cell.
3. Mitochondria - where oxidative phosphorylation and production of ATP occurs
4. Proteins - the structural proteins forming the cytoskeleton and enzymes involved in the metabolic processes of the cell

Question 5

Outline the steps involved in reversible hypoxic injury.

Answer 5

1. Cell becomes deprived of oxygen and there is decreased production of ATP by oxidative phosphorylation
2. When the levels of ATP in the cell drop to less than 5-10% of the normal concentrations, vital cellular functions become compromised
3. There is loss of activity of the Na+/K+ membrane pump which is energy dependent. As the intracellular concentration of Na+ rises, water enters the cell and the cell and its organelles swell up (oncosis). Calcium also enters the cell and this results in damage to cell components
4. With the lack of oxygen, the cell switches to the glycolytic pathway of ATP production. This results in the accumulation of lactic acid which reduces the pH within the cell. The low pH affects the activity of many enzymes in the cell. Chromatin clumping is seen
5. Ribosomes detach from the endoplasmic reticulum (energy is required to keep them attached). Protein synthesis is disrupted. This can result in intracellular accumulation of substances such as fat and denatured proteins

Question 6

Which enzymes does calcium activate in irreversible hypoxic injury and how do they worsen the current state of injury?

Answer 6

1. Phospholipases: causing cell membranes to lose phospholipid,
2. Proteases: damaging cytoskeletal structures and attacking
   membrane proteins,
3. ATPase, causing more loss of ATP,
4. Endonucleases: causing the nuclear chromatin to clump and damaging DNA

Question 7

What are the three main free radicals found in biological systems?

Answer 7

1. Hydroxyl: OH - most dangerous
2. O2-: Superoxide
3. H2O2: Hydrogen peroxide

Question 8

Outline the mechanisms by which the hydroxyl free radical can be produced in cells.

Answer 8

1. Radiation can directly lyse water to form the hydroxyl radical
2. The Fenton and Haber Weiss reactions produce OH. H2O2 and O2- are substrates for these reactions. This is one reason why it is important to rapidly remove O2- and H2O2 so that the more dangerous OH cannot be generated. The Fenton reaction is important in injury where bleeding occurs as when blood is around, iron is available for the production of free radicals

Question 9

Name some examples of constituents of the antioxidant system.

Answer 9

1. Enzymes:
   • Superoxide dismutase
   • Catalases and peroxidases
2. Free radical scavengers:
   • Neutralize free radicals
   • E.g. Vitamins A, C, E and glutathione
3. Storage proteins:
   • Sequester transition metals in the extracellular matrix
   • Transferrin and ceruloplasmin sequester Fe and Cu: these catalyze the formation of free radicals

Question 10

State an example of a heat shock protein.

Answer 10

Ubiquitin

Question 11

Outline the functions of heat shock proteins.

Answer 11

1. They are important when folding in protein synthesis occurs incorrectly or when proteins are denatured during cell injury
2. HSPs recognize proteins that are incorrectly folded and repair them, by ensuring they are re-folded correctly. If this is not possible, the misfolded protein is destroyed
3. HSPs play an important role in cell injury: they maintain protein viability and thus maximize cell survival