How why Damage occur
DNA damage
The
nuclear membrane is crossed by several factors which regulate the gene
expression and repair the DNA damage as soon as it occurs.
Mitochondrial damage
Mitochondrial damage causing ATP depletion.
Cell membrane damage disturbing the metabolic and
trans-membrane exchanges.
ATP Damage
Decreased
generation of cellular ATP: Damage by ischaemia versus hypoxia from other
causes. All living cells require continuous supply of oxygen to produce ATP
which is essentially required for a variety of cellular functions (e.g.
membrane transport, protein synthesis, and lipid synthesis and phospholipid
metabolism).
Damage to membrane pumps
Damage to plasma membrane pumps: Hydropic swelling and
other membrane changes. Lack of ATP interferes in generation of phospholipids
from the cellular fatty acids which are required for continuous repair of
membranes. This results in damage to membrane pumps operating for regulation of
sodium and calcium
Failure
of sodium-potassium pump. Normally, the energy (ATP)-dependent sodium pump
(Na+-K+ ATPase) operating at the plasma membrane allows active transport of
sodium out of the cell and diffusion of potassium into the cell.
cell Membrane damage
Failure of calcium pump: Membrane damage causes disturbance
in the calcium ion exchange across the cell membrane. Excess of calcium moves
into the cell (i.e. calcium influx), particularly in the mitochondria, causing
its swelling and deposition of phospholipid-rich amorphous densities. Ultra
structural evidence of reversible cell membrane damage is seen in the form of
loss of micro villi, Persistence of ischaemia or hypoxia results in
irreversible damage to the structure and function of the cell (cell death).
Mitochondrial damage
Calcium influx: Mitochondrial damage. As a result of
continued hypoxia, a large cytosolic influx of calcium ions occurs, especially
after reperfusion of irreversibly injured cell. Excess intracellular calcium
collects in the mitochondria disabling its function. Morphologically,
mitochondrial changes are vacuoles in the mitochondria and deposits of
amorphous calcium salts in the mitochondrial matrix.
Membrane damage
Activated phospholipases: Membrane damage. Damage to membrane
function in general, and plasma membrane in particular, is the most important
event in irreversible cell injury in ischaemia. As a result of sustained
ischaemia, there is increased cytosolic influx of calcium in the cell.
Increased calcium activates endogenous phospholipases.
Cytoskeleton damage
Intracellular proteases: Cytoskeleton damage. The normal
cytoskeleton of the cell (microfilaments, microtubules and intermediate filaments) which anchors
the cell membrane is damaged due to degradation by activated intracellular
proteases or by physical effect of cell swelling producing irreversible cell
membrane injury.
Nuclear damage
Activated
endonucleases: Nuclear damage. The nucleoproteins are damaged by the
activated lysosomal enzymes such as proteases and endonucleases. Irreversible
damage to the nucleus can be in three forms:
Pyknosis: Condensation and clumping of nucleus
which becomes dark basophilic.
Karyorrhexis: Nuclear fragmentation in to small bits
dispersed in the cytoplasm.
Karyolysis: Dissolution of the nucleus.
Lysosomal damage
Lysosomal hydrolytic enzymes: Lysosomal damage, cell death and phagocytosis. The lysosomal
membranes are damaged and result in
escape of lysosomal hydrolytic enzymes. These enzymes are activated due to lack
of oxygen in the cell and acidic pH. These hydrolytic enzymes include: hydrolase,
RNAase, DNAase, protease, glycosidase, phosphatase, lipase, amylase, cathepsin
etc) which on activation bring about enzymatic digestion of cellular components
and hence cell death. The dead cell is eventually replaced by masses of
phospholipids called myelin figures which are either phagocytosed by
macrophages or there may be formation of calcium soaps.
Membrane damage
CALCIUM OVERLOAD: Upon
restoration of blood supply, the ischaemic cell is further bathed by the blood
fluid that has more calcium ions at a time when the ATP stores of the cell are
low. This results in further calcium overload on the already injured cells,
triggering lipid peroxidation of the membrane causing further membrane damage. Free
radicals(o, H, oH) may produce membrane damage. This reaction is termed lipid
peroxidation. The lipid peroxides are decomposed by transition metals such as
iron. Lipid peroxidation is propagated to other sites causing widespread
membrane damage and destruction of organelles.
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