(From Pathology First Week, Sept 2000, by Brian Buschman)
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There are two principle patterns of cell death:
1) Necrosis is the most common type of cell death which is manifest by swelling, denaturation, coagulation of proteins, breakdown of organelles and cell rupture.
2) Apoptosis is programmed cell death brought on by condensation of chromatin and fragmentation of the cell.
Cellular injury can be caused by:
1) Hypoxia resulting from:
a. Ischema
b. Inadequate oxygenation
c. Loss of O2-carrying capacity
2) Physical agents like trauma, temp or shock.
3) Chemical agents
4) Infectious agents
5) Immunologic reactions
6) Genetic derangements
7) Nutritional deficiencies
Ischemic injuries are what we will use as the example of reversible and irreversible injury.
The first problem with hypoxia is the loss of oxidative phosphorylation. Decreased ATP uses up intracellular energy stores and reduces pH. This results in clumping of the chromatin, swelling and loss of Na+, K+-ATPase (because of loss of ATP production).
Signs of reversible injury include:
1) Plasma membrane blebs
2) General Swelling
3) Clumping of chromatin
4) Lysosomal autophagy
5) ER/Mitochondrial swelling
6) Dispersion of ribosomes
Extensive damage will lead to irreversible injury which is characterized by man things centered around ATP depletion and cell membrane damage. They include:
1) Mitochondria vacuolization
2) P.M. Damage
3) Lysosome swelling
4) Amorphous densities in the mitochondria
5) Leakage of lysosomal enzymes into the cell.
6) Myelin figures
7) Nuclear changes:
a. Pyknosis is the shrinking of the nucleus making it look small and dark.
b. Karyolysis is swelling of the nucleus and loss of the chromatin’s ability to bind die.
c. Karyorrhexis is the fragmentation of the nucleus.
Cell membrane damage results from:
1) Progressive loss of phospholipids cause by activation of Ca2+ dependant phospholipase A2 and decreased phospholipid production with low ATP. More damage leads to more Ca2+ influx.
2) Cytoskeletal damage caused by Ca2+-dependant proteases. It may break intermediate filaments causing cell rupture.
3) Free radicals cause reperfusion injuries when blood flow is restored to ischemic tissues. The blood flow brings in polymorphonuclear leukocytes that produce the reactive oxygen species.
4) Lipid breakdown products from degradation of membranes accumulate and are toxic to membranes.
5) Loss of AAs that are needed.
H2O2 is produced by oxidase and superoxide dismutase and it’s broken down by catalaze. They also come from transition metals, NO derivatives and such. They cause redox damage to cell parts which is a problem.
CCl4 is converted by P-450 to CCl3- which is bad to the membranes. Acetamephin is converted to bad products which cause liver damage. Other chemicals act directly such as HgCl2.
Necrosis is caused by progressive degradation by enzymes on the lethally injured cell. This is where some cells enter the irreversible damage stage. There are several types of necrosis:
1) Coagulation necrosis is a cell death resulting from autolysis of proteins and heterolysis. It is the most common form of necrosis in all body parts except for the CNS. In coagulation necrosis the cellular outline is preserved.
2) Liquefactive necrosis is the primary necrotic form in the CNS where autolysis and heterolysis liquefy the cells. It’s often a result of bacterial infection in the body or hypoxia in the CNS.
3) Gangrenous necrosis.
4) Caseous necrosis involves tuberculosis legions that appear white and “cheese like.”
5) Fat necrosis is an enzymatic degradation of adipose cells often associated with Ca2+ deposits.
Apoptosis is programmed cell death involving:
1) Cell shrinkage.
2) Chromatin condensation
3) Cytoplasmic blebs
4) Phagocytosis of blebs by neighboring cells
5) LACK OF INFLAMATION
It’s biochemical mechanisms of action include:
1) Protein cleavage via caspases to disrupt the cytoskeleton.
2) Cytoplasmic proteins are converted to apoptotic bodies.
3) DNA breakdown
4) Phagocytosis
Heterophagy is the uptake of extracellular material for digestion.
Autophagy is the uptake of intracellular material into vacuoles for digestion.
These two leave lipofuschin granules from undigested particles.
In cases of injury the mitochondria undergo hypertrophy followed by atrophy. There may be excess mitochondria in mitochondrial myopathies which are also seen in tumors called oncocytomas.
When things in the cell go wrong the cytoskeletal machinery messes up. And they are unable to do their normal job. That includes:
a. Keratin for epithelium
b. Neurofilaments for neurons
c. Desmin for muscle
d. Vimentin for C.T.
e. Glial for astrocytes.
Mallory bodies are bundles of keratin associated with alcoholism.
There are neurofibrillary tangles associated with Alzheimer’s.
Hyaline change refers to any change in or around cells resulting in an acidophilic, glassy membrane.
Intracellular hyaline may include:
Extracellular hyaline may include:
Alterations associated with aging include:
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