Irreversible Cell Injury, Mechanism And Morphology

IRREVERSIBLE CELL INJURY, MECHANISM AND MORPHOLOGY

IRREVERSIBLE CELL INJURY:Persistence of ischaemia or hypoxia results in irreversible damage to the structure and function of the cell (cell death). Th e stage at which this point of no return or irreversibility is reached from reversible cell injury is unclear but the sequence of events is a continuation of reversibly injured cell. Two essential phenomena always distinguish irreversible from reversible cell injury 

 Inability of the cell to reverse mitochondrial dysfunction on re-perfusion or re-oxygenation. 

 Disturbance in cell membrane function in general, and in plasma membrane in particular.

SEQUENCE OF CHANGES IN IRREVERSIBLE CELL INJURY

1. 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. Morphological changes are in the form of vacuoles in the mitochondria and deposits of amorphous calcium salts in the mitochondrial matrix.

2. Activated phospholipases: Membrane damage Damage to membrane function in general, and plasma membrane in particular, is the most important event in irreversible cell injury. Increased cytosolic influx of calcium in the cell activates endogenous phospholipases. These, in turn, degrade membrane phospholipids progressively which are the main constituent of the lipid bilayer membrane. Besides, there is also decreased replacement synthesis of membrane phospholipids due to reduced ATP. Other lytic enzyme which is activated is ATPase which causes further depletion of ATP. 

3. Intracellular proteases: Cytoskeletal damage The normal cytoskeleton of the cell (micro filaments, micro tubules 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. 

4. Activated endonucleases: Nuclear damage DNA or nucleoproteins are damaged by the activated lysosomal enzymes such as proteases and endonucleases. Irreversible damage to the nucleus can be in three forms:

i) Pyknosis: Condensation and clumping of nucleus which becomes dark basophilic. 

ii) Karyorrhexis: Nuclear fragmentation in to small bits dispersed in the cytoplasm. 

iii) Karyolysis: Dissolution of the nucleus. Damaged DNA activates proapoptotic proteins leading the cell to death. 

5. 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: (e.g. hydrolase, RNAase, DNAase, protease, glycosidase, phosphatase, lipase, amylase, cathepsin etc) 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.

MORPHOLOGY OF IRREVERSIBLE CELL INJURY    (CELL DEATH)

Cell death is a state of irreversible injury. It may occur in the living body as a local or focal change (i.e. autolysis, necrosis and apoptosis) and the changes that follow it (i.e. gangrene and pathologic calcification), or result in end of the life (somatic death). 

AUTOLYSIS 

Autolysis (i.e. self-digestion) is disintegration of the cell by its own hydrolytic enzymes liberated from lysosomes. Autolysis can occur in the living body when it is surrounded by inflammatory reaction (vital reaction), but the term is generally used for postmortem change in which there is complete absence of surrounding inflammatory response. Autolysis is rapid in some tissues rich in hydrolytic enzymes such as in the pancreas, and gastric mucosa; intermediate in tissues like the heart, liver and kidney; and slow in fibrous tissue. Morphologically, autolysis is identified by homogeneous and eosinophilic cytoplasm with loss of cellular details and remains of cell as debris.

NECROSIS

Necrosis is defined as a localised area of death of tissue followed later by degradation of tissue by hydrolytic enzymes liberated from dead cells; it is invariably accompanied by inflammatory reaction. Necrosis can be caused by various agents such as hypoxia, chemical and physical agents, microbial agents, immunological injury, etc. Based on etiology and morphologic appearance, there are 5 types of necrosis

1. Coagulative Necrosis

2. Liquefaction Necrosis

3. Caseous Necrosis

4. Fat Necrosis

5. Fibrinoid Necrosis 

APOPTOSIS

 Apoptosis is a form of ‘coordinated and internally programmed cell death’ having significance in a variety of physiologic and pathologic conditions. The term was first introduced in 1972 distinct from necrosis by being controlled and regulated cell death, and opposed to that of mitosis by having regulated size of the cell turn over. When the cell is not needed, pathway of cell death is activated (‘cell suicide’). Unlike necrosis, apoptosis is not accompanied by any inflammation and collateral tissue damage. 

MORPHOLOGIC FEATURES: The characteristic morphologic changes in apoptosis by light microscopy and electron microscopy are

1. Involvement of single cells or small clusters of cells in the background of viable cells.

2. Apoptotic cells are round to oval shrunken masses of intensely eosinophilic cytoplasm (mummified cell) containing shrunken or almost-normal organelles.

3. Nuclear chromatin is condensed under the nuclear membrane i.e. pyknosis.    

4. The cell membrane may show blebs or projections on the surface. 

5. There may be formation of membrane-bound nearspherical bodies containing condensed organelles around the cell called apoptotic bodies.                 

6. Characteristically, unlike necrosis, there is no acute inflammatory reaction around apoptosis. 

7. Phagocytosis of apoptotic bodies by macrophages takes place at varying speed. There may be swift phagocytosis, or loosely floating apoptotic cells after losing contact with each other and basement membrane as single cells, or may result in major cell loss in the tissue without significant change in the overall tissue structure.