Lecture 6: Cell injury - reversible effects

Question 1

Physical Damage to DNA

Answer 1

Ionising Radiation (free radicals interfere with DNA causing DNA strands to break), UV radiation (cross linking of pyrimidines)

Question 2

Chemical damage to DNA

Answer 2

Alkylation (i.e. aflatoxin B1) - binds and modifies DNA structure, G -> T transversions.

Question 3

Biological damage to DNA

Answer 3

Dietary Deficiency (i.e. folic acid - B4, Cobalamin - B12) - necessary for DNA synthesis or repair, essential for making Thiamine and methionine (start AA).

Question 4

Physical damage to lipids

Answer 4

Crystals

Question 5

Chemical damage to lipids

Answer 5

Oxidants - ROS

Question 6

Biological damage to lipids

Answer 6

Lipases - i.e. organ damage due to leakage of phospholipases

Question 7

Physical damage to proteins

Answer 7

Heat - denatured proteins, activate heat shock proteins (chaperones) to stop aggregation of proteins, restructure proteins, and reintroduce the unction of those proteins. If not possible, tag for destruction

Question 8

Chemical damage to proteins

Answer 8

Glycation (addition of sugar to proteins) -> malliard reaction

D-glucose + primary amine –> Schiff base –> Amadori product –> Advanced glycation end (AGE) product.

Accumulation of AGE causes proteins to not function properly.

Question 9

Biological damage to proteins

Answer 9

Proteases (i.e. inflammation)

proteases released during inflammation, cleave specific structural proteins.

i.e. Arthritis: accumulation of proteases that cleave collagen in joints

i.e. Emphysema: accumulation of proteases that cleave elastin in lung ECM

i.e. Cancer invasion: “ “ “ cleave laminin, allowing cancer cells to migrate, change shape, location, and function of cells.

Question 10

ROS functions

Answer 10

• Mitochondria reduce O2 to ROS as a part of respiration (ETC), and are essential intermediates in other enzyme reactions
• neutrophils release ROS to kill bacteria.
• React with lipids and proteins within cell and cause cell death.
• act as signalling molecules to promote DNA replication and proliferation.

Question 11

How does ROS injure cell?

Answer 11

• Hydroxyl radicals react with lipid hydrogens to cause lipid peroxidation (modification of hydrogen groups, issues with membrane structure).

Membrane structure:
- increased rigidity (no longer malleable)
- decreased activity of protein enzymes (i.e. sodium pumps).
- altered activity of membrane receptors.
- make cells leaky (increased membrane permeability).

• O2 therapy in babies leads to lung damage
• Inflammation mediated by macrophages and neutrophils
• UV radiation excites molecules, transferring energy to O2, causing skin damage
• Ionising radiation includes hydroxyl radiation.

Question 12

AGE (Advanced glycation end) product

Answer 12

• Inhibits protein function
• causes proteins to cross-link, making them insoluble/precipitate.
• generates ROS (thus interfering with lipids and proteins too).
• binds to cell surface receptors (RAGE), and signals cause blood flow and inflammation.
• accumulates in diabetes (more sugar available)
• cardiovascular disease
  -neurodegeneration in brain (i.e. alzheimers) through insoluble proteins blocking neural function
• cataract in lens through protein deposition.

Question 13

What are the reversible injuries/effects through which cells can adapt, survive, and recover?

Answer 13

Acute intracellular oedema (hydropic change, cell swelling).

Abnormal storage (fatty acids)

Response to stress

Question 14

Acute intracellular oedema

Answer 14

Injury due to increased P.M. permeability (i.e. lipid peroxidation - ROS).

NA/K pump ATPase damaged, ATP synthesis disrupted in mitochondria. ATPase reduces activity.

K+ leaks out of the cell and Na+ into the cell, osmotic gradient balance, cells and organelles visibly reduce swelling.

If swelling is excessive, cell death mechanism.

Question 15

Abnormal storage

Answer 15

Cell cannot process molecules, causing accumulation of fats and glycogen. i.e. Steatosis - ^storage of fats in hepatocytes.

Diabetes: ^conc of fatty acids from adipose tissue
Alcohol: damaged hepatocyte mitochondria’s ability to breakdown TGC (fats).
Kwashiorkor: malnutrition due to inability to transport TGC as VLDL.

Question 16

Adaptive response to stress

Answer 16

Respond differently as per stressor - which bind to receptor, enabling transcription of genes.

Inducer of stresses: DNA Damage Response (DDR), Proteotoxic (heat shock), Hypoxia, Antioxidant response, Unfolded protein response (UPR).

Question 17

Adaptive response to stressor: DNA Damage Response (DDR)

Answer 17

Transcription factor - p53 detects breaks in DNA strands and induces DNA repair to occur before mitosis and S phase (dna synthesis).

Failure to repair DNA can lead to cell death - apoptosis.

Question 18

Adaptive response to stressor: Proteotoxic response (heat shock)

Answer 18

Triggered by accumulation of unfolded, denatured, aggregated proteins. Transcription factor HSF1 activates transcription of chaperone proteins and HSP (heat shock proteins) which:

• promote folding of denatured proteins
• target damaged proteins for destruction
• prevent protein aggregation which is cytotoxic.

Question 19

Adaptive response to stressor: Hypoxia

Answer 19

Transcription factor: HIFa, induced by low O2. Induces proteins active in glucose transport and glycolysis, RBC production, Blood vessel production (VEGF).

Process supports capacity of O2 transfer on RBC, and create new B.V. to transport blood to ischaemic/hypoxic tissues.

Question 20

Adaptive response to stressor: Antioxidant response

Answer 20

Triggered through detection of oxidative stress and regulation of ROS to upregulate antioxidant enzymes to rebalance redox homeostasis.

Question 21

Adaptive response to stressor: Unfolded protein response (UPR)

Answer 21

Triggered by unfolded/denatured proteins in ER. Induces production of chaperones, suppresses global protein synthesis, induces ERAD (ER-associated degradation), promotes autophagy to eliminate aggregated proteins.