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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