Lecture 3: Cell injury, Inflammation and Healing, Part 1

Question 1

Summarise cellular response to stress and injury;

Answer 1

Mild injurious agent or minor stress i.e rapidly altered environmental conditions, cells might be able to adapt and/or its reversible.

If the injurious agent or stress exceeds the cells adaptive capacity the cell suffers irreversible cell injury and is killed outright or induced to commit suicide.

Question 2

What causes cell stress and injury?

Answer 2

• Physical
• Chemical
• Biological i.e microbes
• Immunological i.e autoimmune
• Genetic derangements i.e congenital or predispositions
• Nutrient imbalances

Question 3

What are the six mechanisms of cell injury on an individual cell?

Answer 3

1) Reduced energy production
2) Damage to cell membranes
3) Increased cytosolic Ca concentrations
4) Damage due to free radicals
5) Damage to proteins
6) Damage to nuclear or mitochondrial DNA

Question 4

Describe the mechanisms of reduced energy production in cellular damage;

Answer 4

Lack of oxygen or damaged enzymes, cytoplasm, mitochondria can result in ATP depletion = Damage

• Cant repair
• ATP dependant pumps = Na, Water influx, swelling, Ca influx is very damaging
• Cant make proteins

Question 5

What can damage cell membranes?

Answer 5

• Free radicals
• Hypoxia
• Bacterial toxins
• Failure of plasma membrane Ca

Question 6

Describe how damage to cell membrane results in overall cell damage;

Answer 6

• Influx fluid, ions,
• Loss of cellular contents through leakage
• Membrane pumps damage, loss of osmotic control
• Damaged lysosomal membrane, loss of enzymes = autolysis
• Mitochondrial membrane damage, (Cyto C release = apoptosis) also loss of Energy

Question 7

How does increased cytosolic Ca cause Cell damage?

Answer 7

• Loss of Ca ATPase = Ca influx and activation of destructive Ca dependant enzymes i.e
• ATPases (ATP depletion)
• Phospholipases
• Proteases
• Endonucleases (DNA and Chromatin fragmentation)

Question 8

How do free radicals cause cellular damage?

Answer 8

• Secondary form of cell injury i.e oxidative stress

Free radicals cause damage by: (Autocatalytic)

• Attacking the double bonds in unsaturated FA in membranes
• Oxidising AA residue side chains in proteins
• Reacting with thymine in nuclear and mitochondrial DNA

Question 9

How does damage to proteins result in cell damage?

Answer 9

Loss of key proteins i.e loss of DNA/protein repair enzymes

• Damage to proteins by free radicals or glycation

Question 10

How can nuclear or mitochondrial DNA be damaged?

Answer 10

• Ionizing radiation (breaks chemical bonds)
• UV
• Chemical agents
• Genetic
• Nutritional deficiency

Question 11

What are two generic factors activated when cells experience stress?

Answer 11

Heat shock factors -> Heat shock proteins (molecular chaperones which assist in the repair of damaged proteins in the cells

Stress kinases -> i.e p38 MAP kinase, initiate signalling cascades that co-ordinate a cells response to damage.

Question 12

In general, cells respond to different stressors with different activation of signalling pathways, what are four examples of this;

Answer 12

• p53; Senses DNA damage, and initiates either a halt in cell division (repair) or apoptosis
• BMF; Involved in response to actin cytoskeleton damage
• Bim is involved in response to microtubule damage
• Bad is involved in cell stress due to inadequate stimulation by growth factors.

Question 13

What are some adaptive cellular responses?

Answer 13

• Hypertrophy and hyperplasia
• Atrophy
• Metaplasia

Question 14

What is the point of no return for cellular injury?

Answer 14

Severe injury results in cells inability to reverse membrane potential and mitochondrial dysfunction event after the injurious stimulus is removed.

Question 15

What are the two types of cell death?

Answer 15

Necrosis and apoptosis

Question 16

Write some notes on necrosis;

Answer 16

• Does not require energy
• Affects many cells
• Membrane lysis and leakage of cytoslic enzymes which digest cellular components
• Leaked cellular contents also generates inflam response.
• Uncontrolled and always pathological

Question 17

Describe the appearance of necrotic cells;

Answer 17

• Cytoplasm is featureless
• Fragmented nuclei i.e chromatin
• Usually cells phagocytosed within a day otherwise can cause precipitation of Ca (dystrophic calcification)

Question 18

What is apoptosis? When does it occur? What does it require?

Answer 18

• Controlled cell death
• Following sufficient irreversible cell damage
• Requires energy, so early process involves destruction of high energy cellular machinery such as DNA repair enzymes.

Question 19

When is apoptosis especially common?

Answer 19

• Following DNA damage because lack of proteins, growth factors, hypoxia

Question 20

When does apoptosis play a critical role?

Answer 20

• Terminally injured cells
• Viral infected cells
• Neoplastic cells
• Self reactive immune system cells

Question 21

Describe apoptotic blebs;

Answer 21

During apoptosis, chromatin is cleaved and condensed and membrane bound blebs containing cytosolic contents and organelles break off the cell and are phagocytosed by neighbouring cells or specialised immune cells. Cytosolic contents do not leak into the extracellular space therefore inflammation is not initiated.

Question 22

How are the caspases involved in apoptosis?

Answer 22

• A cascade of enzymes known as caspases mediates many of the events of apoptosis. i.e caspase 3 digests cellular proteins and activates other enzymes.