Mechanism of injury Flashcards
(11 cards)
Explain how cell and injury-specific factors affect the progression from reversible to irreversible injury
- Recovery from reversible injury
- Injury has compromised cell function
- Recovery if the damaging stimulus is removed
- May compromise organ function
- Reversibly injured myocytes (transient ischemia) may be transiently non-contractile which will affect the function of the heart - Cell death from irreversible injury
- When the cell cannot recover, it dies
- Two types of cell death which differ in morphology, cause and roles in disease
> Necrosis
> Apoptosis
- May have occurred before morphological changes become visible
Understand the principles of haematoxylin and eosin staining
Morphology:
- Gross or microscopic appearance of cells or tissues
- Most cells are transparent
- Staining procedures make cells visible:
o E.g. Triphenyl tetrazolium chloride colours viable myocardium magenta
- Haematoxylin staining
- stains nucleus purple
- Haematoxylin can be considered as a basic dye:
- It is used to stain acidic (or basophilic) structures a purplish blue
- Stains nucleic acids (DNA in nucleus, RNA in ribosomes and RER) - Eosin staining
- stains cytoplasm pink
- It stains basic (or acidophilic) structures red or pink (also sometimes termed ‘eosinophilic’)
- Most proteins
Recognise the morphological features of reversible and irreversible injury
- Irreversible injury
- Occurs when mitochondrial function can’t be recovered
- And when membranes lose their structural integrity:
o Lysosomal membranes
> Contents leak into the cell
> Nuclear and cytoplasmic components degraded
o Plasma membrane
> Loss of osmotic balance
> Cellular contents leak into extracellular space (inflammation)
o Mitochondrial membrane
> Mitochondrial dysfunction
Recognise the point at which injury becomes irreversible
Cell type response to ischemia
1. skeletal muscle (2-3 hours)
2. Cardiac muscle (20-30 minutes)
3. Neurons (3-5 minutes)
- The point at which injury becomes irreversible depends on the duration and severity of the injury
> E.g. short, low dose exposure/severity of toxin
Explain the mechanisms of cell injury
Result in abnormalities of essential cellular components
o Mitochondria
o Plasma membrane
o DNA and Proteins
Mechanism of cell injury:
- Decreased ATP
- Damage to mitochondria
- Influx of calcium
- Accumulation of ROS
- Membrane damage
- DNA and Protein damge
*Note:
- The mechanism of injury is the same, but severity and duration decide the outcome:
Reversible or Irreversible (onto cell death mechanisms - necrosis and apoptosis)
- The extent to which the cell injury mechanism proceeds determines the liklihood of it turning into irreversible injury and hence cell death
- Each step of cell injury mechanism is exscalating cell injury - once step 5/6 are reached (membrane damage & DNA/protein damage) the cell is essentially irreversibly injury
Describe Step 1 of cell injury (Lower ATP)
- usually a result of hypoxia
- reduced oxygen supply causes the activity of ETC to decrease causing a reduction in ATP synthesis
- activity of the sodium-potassium pump depends on ATP so decreased activity of the pump will lead to influx of sodium ions into cell
- water tends to follow sodium, so water will also travel into cell and so cell will swell
- hypoxia increases anaerobic glycolysis which increases accumulation of lactic acid inside cell causing reduction in intracellular pH
- this decreases enzymatic activity
- Hypoxia also causes failure of calcium pumps
- causing excessive calcium influx
- ATP depletion causes ribosomes to detach from ER leading to reduction in protein synthesis
Describe Step 2 of cell injury (mitochondrial damage)
Mitochondria can be damaged by:
1. Accumulation of ROS
2. Influx of Ca
Two major consequences of mitochondrial damage:
1. formation of high conduction mitochondrial permeability transition pores
- these channels allow calcium ions to leak out freely into cytosol causing loss of mitochondrial membrane potential
- This impairs oxidative phosphorylation causing further reduction in ATP synthesis
2. Release of apoptotic proteins and enzymes:
- Cytochrome C
- Caspases
Describe Step 3 of cell injury (Influx of Ca)
- free cytosolic calcium conc is maintained at very low level
- main intracellular calcium ion stores are the ER in the mitochondria
- calcium acts as an activator for a large number of enzymes:
> phospholypases: cell membrane damage
> Endonucleases: DNA and chromatin fragmentation
> Proteases: breakdown of membrane and cytoskeletal proteins
> ATPases: hydrolyse ATP - calcium ions also activate apoptotic proteins and enzymes and promote apoptosis
Describe Step 4 of cell injury (accumulation of ROS)
- free radicals contain unpaired electrons and are highly unstable
- they donate or gain electrons from cellular components while causing damage to them
Describe Step 5 of cell injury (membrane damage)
- membranes can be damaged by reactive oxygen species whcih cause lipid peroxidation
- decreased phospholipid synthesis due to reduced ATP synthesis
- increased phospholipid breakdown (phospholipase activity)
- cytoskeleton abnormalities (protease activity)
> plasma membrane
- loss of osmotic balance
- influx of fluids and ions
- loss of cellular contents
> lysosomal damage
- release of lysosomal enzymes
> mitochondrial membrane damage
- mitochondrial permeability transition pores
-
Describe Step 6 of cell injury (DNA & Protein damage)
Protein and DNA damage:
- DNA damage
o Caused by drugs, radiation or oxidative stress (ROS)
- Protein damage/misfolding
o Caused by inherited mutations and external triggers ie ROS
- Initiates suicide program if it cannot be repaired apoptosis
