Mechanisms of cell injury and cell death

Question 1

General pathogenesis of cell injury reason?

Answer 1

Perturbation of homeostasis

Question 2

Three general ways that cells usually cope with injury

Answer 2

1. Adaption
   reversible functional structural responses
   = resulting in new but altered steady states
   2 Degernation
   3 Death (necrosis or apoptosis)

Question 3

The two end result responses to injury.

Answer 3

1. Reversible
   after injury, the cell can be restored to normal or near-normal cellular stx + fx
   Look for nucleus
2. Irreversible
   progression to death
   Irreparable DNA damage = (senescence) permanent growth arrest or cell death or neoplastic transformation

Question 4

List 6 final common biochemical mechanisms leading to cell injury

Answer 4

ATP depletion
Mitochondrial damage
Entry of calcium
Oxidative stress ( Reactive oxygen stress- lipids, proteins and DNA)
Defects in membrane permeability 
Damage to DNA

Question 5

List things that lead to progression of cell death (9)

Answer 5

oxygen deficiency, physical agents, infectious microbes, nutritional imbalances, genetic derangement, workload imbalance, chemical/drugs/toxins, immunological dysfunctions, ageing

Question 6

ATP depletion major causes

Answer 6

Major cause =
reduced supply of oxygen and nutrients
mitochondrial damage
actions of some toxins

Question 7

ATP depletion, at what point is it classified as this?

Answer 7

Depletion of ATP to 5%-10% of normal level = widespread effects on many critical cellular systems

Question 8

what are three things ATP depletion causes?

Answer 8

cell swelling
cellular energy metabolism is altered
Structural disruption fo protein synthetic apparatus

Question 9

Explain how cell swelling occurs with ATP depletion

Answer 9

sodium/ potassium pumps require ATP to fx properly
- mal Fx of sodium pump causes swelling because
sodium accumulates and potassium diffuses out
results CELL SWELLING

Question 10

explain how ATP depletion alters cellular energy metabolism

Answer 10

as ATP is required for Aerobic ATP synthesis, the body copes by increasing anaerobic glycolysis which increase lactic acid levels.
Lowing the PH then results in decreased enzyme activity

Question 11

explain how ATP depletion causes structural disruption of protein synthetic apparatus

Answer 11

occurs when prolonged deletion of ATP
The apparatus which are used for protein synthesis
Eg - ribosome detach from rER and dissociation of polysomes
End result is reduced protein synthesis

Question 12

Mitochondrial damage explain the three consequences and why mitochondria is often susceptible to damage

Answer 12

Mitochondria are sensitive to lots of stimuli
Including - hypoxia and toxins

the three consequences

1. forming high-conductance channel in the mitochondria membrane
   - = loss of mitochondrial membrane potential = inability of oxidative phosphorylation = ATP insufficiency = necrosis of cells
2. abnormal oxidative phosphorylation
   - - leads to formation fo reactive oxygen species

3.mitochondria sequester between out and inner membrane have cells the apoptosis reaction
protein leaking into cytosol = overall death by apoptosis

Question 13

normal calcium homeostasis

Answer 13

cytosolic free calcium very low 0.1 mmol

Extracellular level 1.3mmol (most in mitochondria + ER)

Question 14

Abnormal Ca homeostasis

Answer 14

Ischaemia and certain toxins = increase cytosolic calcium concentrations
Causing Ca influx
1. First release of calcium from intracellular stores
2. Then after by diffusing across plasma membrane by intracellular calcium

Question 14

Abnormal Ca homeostasis

Answer 14

Ischaemia and certain toxins = increase cytosolic calcium concentrations
Causing Ca influx
1. First release of calcium from intracellular stores
2. Then after by diffusing across plasma membrane by intracellular calcium

Question 15

explain the issues with increased intracellular calcium

Answer 15

1. The increased intracellular calcium leads to:
   activation of # of enzymes—> deletour effects on cell
   Results in excessive activation of enzymes eg
   - phospholipase = membrane damage
   - Proteases = membrane and cytoskeletal proteins
   - Endonuclease = DNA and chromatin fragmentation
   - ATPases = hastening ATP depletion

Question 16

explain another impact of the calcium accumulation intracellular space

Answer 16

2. Accumulation of calcium in mitochondria resulting =
   - opening of mitochondrial permeability transition pore
   - failure of ATP generation

Question 17

Defects in membrane permeability - Four biochemical mechanism contributing to membrane damage during cell injury

Answer 17

Reactive oxygen species

Decreased phospholipid synthesis
- Reduced ATP production —> results in activation of energy-dependent biosynthetic pathways
from defective mitochondrial fx
Hypoxia

Increased phospholipid breakdown
Likely due to calcium levels too high in cytosol, which excessively activates phospholipase

Cytoskeletal abnormalities
Breakdown of cytoskeletal = detachment of cell membrane from it = increased likelihood of stretching rupturing
Cytoskeletal breakdown is often due to calcium homeostasis issues - increase in cytosolic calcium

Question 18

Damage to DNA and proteins- when homeostasis is disturbed the initial reaction?

Answer 18

= acute cell swelling
—> resulting often from hypoxia (ATP depletion) or other things that cause mal fx of Na-K pump —> influx of water and sodium into the cell that causes the swelling

hypoxia —> ATP depletion —> NA-K pump mfx
Lipid peroxidation
Toxin binding
Ion channel damage
Insetting transmembrane pore-foring complexes
eg MAC of complement pathway
Eg bacterial cytolysins

hypoxia —> ATP depletion —> NA-K pump mfx
Lipid peroxidation
Toxin binding
Ion channel damage
Insetting transmembrane pore-foring complexes
eg MAC of complement pathway
Eg bacterial cytolysins