Cell death: Necrosis & Apoptosis

Cells die through either of two distinct processes: necrosis or apoptosis.  Necrosis is death due to unexpected and accidental cell damage.  A number of toxic chemical or physical events can cause necrosis: toxins, radiation, heat, trauma, lack of oxygen due the blockage of blood flow, etc.

These physical or chemical insults can lead to the lethal disruption of cell structure and activity

As necrotic cells begin to die, they swell –  holes appear in the plasma membrane and intracellular materials spill out into the surrounding environment.

Scanning electron micrograph of dying cells

An important side-effect of these changes is the loss of the ability to regulate the intracellular environment. 

The normal intracellular concentration of Ca²⁺ is generally less that 10^-7 M.

The concentration of Ca²⁺ outside the cell is generally much higher, on the order of 10^-3 M.   There are also high levels of Ca²⁺ sequestered within mitochondria and other intracellular compartments.

The low concentration of intracellular Ca²⁺ requires energy to maintain - Ca²⁺ must be pumped out of the cytoplasm. 

As the cell dies, its ability to maintain the integrity of the plasma membrane and to pump ions is lost. 

Ca²⁺ acts as an allosteric effector of many proteins, drastically altering their activity.

Unregulated Ca²⁺ induces the generation of toxic chemicals and activates enzymes that lead to the degradation of cellular molecules.

As the cell is disassembled, various breakdown products are produced and released into the neighborhood.

Among these are derivatives of membrane phospholipids, such as arachidonic acid, which is a free fatty acid or FFA.

The presence of these molecules is interpreted by neighboring cells as a sign of tissue damage.  They react to defend themselves.

The FFAs generated by damaged and dying cells are themselves substrates for enzymes, in particular the cyclooxygenases.

These enzymes transform FFAs into prostaglandins and other molecules, known collectively as eicosanoids, which mediate inflammatory responses.

A number of conditions are characterized by chronic inflammation, for example rheumatoid arthritis.

Left untreated, chronic inflammation will damage tissues irreversibly.  

One way to treat the symptoms of chronic inflammation is to inhibit the enzymes that generate eicosanoids. One class of anti-inflammatory drug are the cyclooxygenase inhibitors. 

There are two different cyclooxygenases, COX1 and COX2, that are normally targeted for inhibition.

Different anti-inflammatory drugs target different COX1 and COX2 differently. 

Aspirin and aspirin-derivatives preferentially inhibit COX1; other drugs, such as indomethacin and rofecoxib (vioxx) are specific for COX2.

• Vasoconstriction halts blood loss; broken capillaries will be sealed by clots. These clots are formed by the proteolysis-based precipitation of specific proteins.
• The damaged cells release cellular breakdown products that act as inflammatory signals – these cause capillaries to dilate and local blood flow to increase.
• There is an increase in tissue temperature and tissue reddening, accompanied by the release of histamines, which cause pain by stimulating pain-sensing neurons.
• There is an increase in capillary permeability, which enables white blood cells, leukocytes and macrophages, to leave the circulatory system and move into the damaged region. 

• Fluid (mostly water) moves from the blood to the tissue, leading to swelling or edema.
• White blood cells congregate, engulf and digest cellular debris, bacteria and other foreign materials.  The immune system will kill and digest foreign organisms from the damaged site.   Dying white blood cells can form pus.
• The tissue will regrow and the wound heal.

• Sometimes chemicals can crystallize in a tissue - why might that lead to necrosis?
• Assume that you add an Ca²⁺ ionophore to a cell and that the ionophore accumulates in the plasma membrane.   How would this mimic the effects of necrosis?
• Why does modifying the aspirin molecule change its selectivity for COX1 over COX2?
• Does inhibiting COXs remove the cause of the inflammation?
• After injury, why is the initial constriction of the blood vessels important?
• What draws immune system cells to the damage site?
• Why, do you think, it might be important to make pain-sensing neurons hypersensitive in the damaged area?  

There is a second process by which cells die, apoptosis. Apoptosis is sometimes called programmed cell death.

Apoptosis originally referred to the process by which leaves falls from trees in the autumn, but it has been adapted to describe this type of non-traumatic cell death.

Apoptosis is a way to remove unwanted cells. During apoptosis, cellular contents are not released and inflammation does not occur.

The apoptotic cells are rapidly engulfed by their neighbors an removed. 

Programmed cell death is a normal and necessary event of normal development.

During the development of the vertebrate nervous system, for example, ~50% of the neurons born die as part of the rewiring process.

Although less complex than eukaryotes, bacteria also have apoptotic mechanisms.

These systems have arisen independently many times, suggesting that they perform valuable functions.

The system is based on a stable toxin and an unstable anti-toxin, together it is known as an addiction module.

If protein synthesis is interrupted, both toxin and anti-toxin synthesis are blocked.

The unstable anti-toxin disappears while the stable toxin persists.

Once the anti-toxin level falls far enough, the toxin become active and kills the cell.

• Why is it not necessary for immune system cells to invade a region undergoing apoptosis (normally)?   Why is it not necessary for immune system cells to invade a region undergoing apoptosis (normally)?  
• What roles, do you think, does apoptosis play in the development of the human nervous system?  
• Why might a prokaryotic cells have a cell death system?