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Mechanisms of Disease > Cell Injury > Flashcards

Flashcards in Cell Injury Deck (19):

What can cause cell injury?

Hypoxia, physical agents, chemical agents, microorganisms, immune mechanisms, dietary insufficiency and genetic abnormalities.


Where does cell injury take place within the cell?

Cell membrane, nucleus, cell proteins and the Mitochondria.


What happens in reversible hypoxia?

As the cell becomes more deprived of oxygen less ATP is produced. When the cell reaches about 5%-10% of its ATP reserves the cell processes requiring it begin to be compromised.
• Loss of function of the Na Pump causing a build-up of sodium in the cell, as a result the cell begins to swell with water (oncosis) and Calcium enters the cell
• Accumulation of lactic acid from anaerobic respiration causes a drop in cellular pH effecting many cell enzymes and causing chromatin to clump together
• Ribosomes detach from mRNA and the ER due to lack of energy and so protein synthesis stops resulting in the build-up of fat and denatured proteins


What happens when hypoxia becomes irreversible?

At some point the cell will eventually die. This is usually due to oncosis causing the tissue to appear necrotic. This happens as the membrane integrity fails causing a large influx of calcium into the cell calcium causes the activation of endonucleases (destroying DNA randomly), proteases damaging the cytoskeleton, ATPases using up more ATP and Phospholipases which damage the cell membrane. Eventually this causes damage to lysosome membranes causing the release of the highly potent lysosomal enzymes. When a cell is put under pressure they almost always begin to synthesise HSP (heat shock Proteins) these are proteins that will go around searching for damaged proteins and try to repair or destroy them the best example of them is Ubiquitin.


What is ischaemic reperfusion injury?

This is when oxygen supply is returned to a cell but causes more damage than if it hadn’t returned. This is probably due to an increase in oxygen free radicals, neutrophils or delivering of complement proteins and activation of the compliment pathway.


What defense mechanisms do we have against free radicals?

• Superoxide Dismutase (SOD) which formed hydrogen peroxide form superoxide
• Catalses and Peroxidases complete this reaction to oxygen and water
• Free Radical Scavengers such as Vit A, C and E and Glutathione
• Storage proteins for iron such as Transferrin and Ceruloplasmin for iron and copper.


What is visible under a light microscope in cell death?

We can use the Dye exclusion technique which inserts dye into or outside of a cell to see it is taken up by the cell and therefore if the cell membrane is intact. Just after dying there may be reduced pink staining of the cytoplasm due to extra water this may be followed by dark pink staining due to the detachment of ribosomes and build-up of denatured cells. Nuclear changes such as clumping (reversible) and Shrinkage (pyknosis), Fragmentation (Karryohexis) and Dissolution (Karryolysis) – all irreversible.


What is visible under an electron microscope in cell death?

Reversible changes such as swelling (both cell and organelles), Cytoplasmic blebs - bulges due to weaknesses, clumped chromatin due to low pH. Ribosomes seperation
Irreversible changes such as Increase cell swelling, Pyknosis, Karyolysis and Karyorrhexis, Swelling and rupture of ribosomes, Memebrane defects, ER lysis and the appearance of Myelin figures.


What is necrosis?

Necrosis - this is the morphological changes that become visible and is usually seen after damage to the cell membrane and lysosomal bursting. The necrotic effects of this usually appears after a few hours and eventually it will be removed completely by degradation and phagocytosis.


What are the two main types of necrosis?

Coagulative is the most common and is when there is more protein denaturation than enzyme release and so this leads to clumping of proteins and a solidity forms. Some of the main membrane architecture may remain causing a ghost outline. This type of necrosis will appear white to the naked eye.

Liquefactive is less common and occurs when there is more enzyme release (particularly proteases) leading to the tissue becoming liquefied and disappearing. This is seen in massive neutrophil invasion and bacterial infections. It is also seen in the brain as this lacks a robust collagenous matrix for support.


What is caseous necrosis?

Caseous Necrosis this is structured by amorphous debris that are not ghost outlines and may appear to look like cheese. It is most common in infections such as TB and is associated with a type of inflammation called granulomatous.


What is fat necrosis?

Fat Necrosis is caused by the damage of fat most commonly seen due to pancreatitis which causes lipases to be released. The free fatty acids then react with calcium to form small waxy droplets.


What is infarction?

Infarction refers to a cause of necrosis - ischaemia. Most of these are due to a thrombus or embolism or sometimes due to external compression. It can be coagulative or liquefactive and may lead to gangrene.


What's the difference between red and white infarcts?

Red or white in appearance depending on how much they were infarcted. Some tissue are only supplied by end arteries meaning there are no other arterial supplies to that area and so will appear white or pale on infarction. A red infarct occurs where there are more than one blood supply to the area or numerous anastomoses, this appears red due to haemorrhage.


What important molecules are released on cell death?

• Potassium – inside a cell normally high potassium so dying cells are considered a potassium bomb.
• Enzymes – can help to indicate the organ involved and how long ago it happened as smallest enzymes released first
• Myoglobin – released from dead myocardium and striated muscle can lead to a condition called rhabdomyolysis where the renal tubules get blocked with myoglobin causing renal failure


What is apoptosis?

This is effectively cell suicide and is seen commonly in natural cases such as during the embryo development, Killer T cell activity and destruction of cells with irreversible DNA damage. It is an active process requiring energy and involves enzymes from the cell degrading the DNA and proteins of the cell in a controlled manner.


What does apoptosis look like under the microscope?

Apoptotic cells appear shrunken under the microscope and they may have an abnormal shaped nucleus as well as appearing dark pink. The cell eventually buds into smaller compartments and are then phagocytosed. There is no leakage of the inside of the cell.


What is the intrinsic mechanism of apoptosis?

This pathways centres around the mitochondria. The most important trigger is a protein called p53 which responds to DNA damage. P53 leads to increased mitochondrial permeability and therefore the release of cytochrome c (normally inhibited from release by Bcl-2) Cytochrome c interacts with APAF1 and caspase 9 to form the apoptosome which activates other caspases down the line.


What is the extrinsic mechanisms of apoptosis?

This is stimulated by extracellular ligands such as TRAIL which bind to death receptors (TRAIL-r) and leads to the formation of the apoptosome and so apoptosis.