Medsci 203 - Cell Injury And Reversible Effects On Cells

Front 1

How does ionising radiation damage DNA?

Back 1

→ X/gamma rays break chemical bonds in DNA cells via radiolysis, turning water into H and OH radicals that cause DNA strands to break.
→ some bonds are able to repair but others undergo 'misrepair' causing incorrect rejoining of DNA causing chromosome translocation
→ bonds that undergo 'toxicity' cause damage to endothelial cells eg. erythema and oedema

Front 2

Erythema

Back 2

acute toxic damage to vascular endothelial cells → cause arterials to dilate hence skin reddening

Front 3

Oedema

Back 3

acute toxic damage to vascular endothelial cells → cause leaking of plasma hence tissue swelling

Front 4

How does UV radiation damage DNA?

Back 4

→ they damage DNA bases causing adjacent pyrimidines (C,T) to become linked
→ if misrepair occurs then a mutation between these bases will occur leading to cancer cells

Front 5

Sunburn

Back 5

→ excessive damage to keratinocytes from UV rays causing cell death

Front 6

How does alkylation damage DNA?

Back 6

→ fungal products such as aflatoxin B1 (AFB1) accumulate in badly stored food
→metabolites alkylate with proteins to cause liver damage (aflatoxicosis)
→ metabolites alkylate with DNA to cause G-T mutations hence liver cancer

Front 7

How do vitamins B9 and B12 deficiency damage DNA?

Back 7

→ B9 (folic acid) and B12 (cyanocobalamin) are needed for DNA synthesis and repair
→ lack of intrinsic factors prevent B12 absorption leading to megaloblastic anaemia

Front 8

Lipids

Back 8

→ provide the cell integrity and produce cell compartments
→ they separate internal and external cell environments

Front 9

How do crystals damage lipids?

Back 9

→ insoluble; eg. silica, asbestos, monosodium urate, cholesterol and hydroxyapatite
→ puncture lysosomal membranes to release hydrolytic enzymes activating inflammasomes

Front 10

How do chemical oxidants damage lipids?

Back 10

→ free radicals and reactive oxygen species undergo oxidative reactions (ROS)
→ superoxide, hydrogen peroxide, hydroxy radical to end with water

Front 11

Describe the oxidative reactions that damage lipids

Back 11

1. Superoxide is detoxified by superoxide dismutase to produce oxygen and hydrogen peroxide (~1% of oxygen consumed by mitochondria
2. Hydrogen peroxide is detoxified by catalase to oxygen and water
3. Hydroxyl radical → most destructive and can damage all biological molecule

Front 12

When can reactive oxygen species damage cells?

Back 12

→ oxygen therapy - high concentration of oxygen to premature babies can cause lung damage
→ inflammation - neutrophils and macrophages
→ UV radiation - excites photosensitisers which transfer energy to oxygen to produce singlet and radical species
→ damage to mitochondria - not able to reduce oxygen completely
→ radiotherapy

Front 13

How does lipid membrane damage occur?

Back 13

→ occurs in chain reactions via carbon chained radicals
1. carbon centered radical
2. lipid peroxyl radical
3. lipid hydroperoxide
4. aldehydes and ketones → toxic

Front 14

How does heat damage proteins?

Back 14

→ temperatures over 42°C can denature proteins which can result in heat shock proteins

Front 15

Glycation/Glycolysation

Back 15

→ occur between reducing sugars + amino groups to generate
1. reversible Schiff bases
2. irreversible Amadori products
3. advanced glycation end products (AGE)

Front 16

How does AGE injure cells?

Back 16

→ inhibit protein function
→ cross linking, aggregating and precipitating proteins (impede axonal transport in neurons)
→ generating reactive oxygen species (ROS)
→ binding to receptors of AGE (RAGE) on vascular and inflammatory cells causing inflammation and reduced blood flow

Front 17

How do proteases damage proteins?

Back 17

→ via proteolytic cleavage in ECF during inflammation causing
1. collagen arthritis
2. elastin emphysema
3. laminin during cancer invasion

Front 18

Acute Intracellular Oedema

Back 18

→ hydropic change causing compromise in regulating ion concentrations in the cytoplasm

Front 19

What causes acute intracellular oedema?

Back 19

1. plasma membrane is more permeable to Na
2. Na/K ATPase is damaged
3. ATP synthesis is disrupted and Na/K ATPase is inhibited → K leaks out of cell and Na leaks in causing cell to swell (initially reversible)

Front 20

Abnormal Storage of Cells

Back 20

→ results in fat and glycogen accumulation in cell storage
1. unmetabolised fatty acids
2. inability of liver cells to oxidise fatty acids (alcohol damage)
3. fatty acids are exported as VLDL (kwashiorkor, severe malnutrition)

Front 21

Adaptive Responses of Cells

Back 21

→ transcription factors activated
→ binding to response elements in gene promoters
→ transcription of gene encoding protective proteins

Front 22

Types of response elements

Back 22

1. DNA damage
2. antioxidant
3. heat shock
4. unfolded proteins
5. hypoxia

Front 23

DNA damage response

Back 23

Inducer: DNA damage, hypoxia, ROS
Transcription Factor: p53
Targets/Effects: regulates DNA repair, cell cycle arrest, apoptosis

Front 24

Antioxidant response

Back 24

Inducer: oxidative stress
Transcription Factor: Nrf2
Targets/Effects: induce genes encoding SOD1 and catalase

Front 25

Heat Shock response

Back 25

Inducer: agents that damage proteins
Transcription Factor: heart shock factors (HSFs)
Targets/Effects: induce chaperone synthesis
1. prevent aggregation (cytotoxic)
2. aid protein renaturation
3. promote proteolytic destruction of acutely damaged proteins

Front 26

Unfolded Protein response

Back 26

Inducer: stressors to ER eg. infection, hypoxia, ROS etc
Transcription Factors: several
Targets/Effects: induces chaperone synthesis

Front 27

Hypoxia response

Back 27

Inducer: hypoxia
Transcription Factors: hypoxia inducible factors (HIFs)
Targets/Effects: allows cells to adapt to hypoxia eg. glucose transporters, glycolytic enzymes, increase erythrocyte and blood vessel efficiency

Front 28

Whats the point of all these responses?

Back 28

To maintain homeostasis within the body