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Biofundamentals -Cell Death: Necrosis and Apoptosis
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Cell death: Necrosis & Apoptosis
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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.
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Biofundamentals -Cell Death: Necrosis and Apoptosis
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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.
Mutational studies indicate that
inflammation is due to eicosanoid
production.
In response to these signals, immune
system cells migrate to the site of
damage and act to combat invading
microorganisms.
In some cases, an underlying pathology
can lead to chronic inflammatory
diseases.
Left untreated, chronic inflammation will damage tissues irreversibly.
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Biofundamentals -Cell Death: Necrosis and Apoptosis
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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.
Necrosis leads to
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
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Biofundamentals -Cell Death: Necrosis and Apoptosis
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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.
The disappearance of the tadpole tail during metamorphosis and the formation of
the fingers of the hand are classic examples of apoptotic processes.
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Biofundamentals -Cell Death: Necrosis and Apoptosis
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Normal cells live on the edge, ready to kill
itself in response to specific sets of signals.
Cells can enter apoptosis as part of normal
development or in response to viral
infection, cellular stress, or DNA damage.
The proteins that mediate the cell death
response are also involved in destroying
aberrant cells, such as cancer cells.
Essentially all cancers accumulate
mutations that inactivate their cell death
pathway.
This enables the cancer cell to replicate
with increasingly aberrant DNA; in the
presence of an intact apoptotic pathway
such a cell would die apoptotically.
Apoptotically dying cells activate a set of
degradative enzymes, the caspases, that
mediate the controlled disassembly and
degradation of the cell.
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Biofundamentals -Cell Death: Necrosis and Apoptosis
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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?
Use Wikipedia | revised 16-Apr-2006
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