Apoptosis and necrosis

When cells are stressed so severely, exposed to inherently damaging agents or suffer from intrinsic abnormality, the cells are no longer able to survive. Such injurious stimuli affects several metabolic pathways and many cellular organelles. Initially the injury may progress through a reversible stage to an irreversible stage.

Reversible cell injury
This is the early stage or mild form of injury. If the injurious agent is removed, the functional and morphological changes can be reversed. Because the injurious agents do not cause membrane damage.

Irreversible cell injury or cell death
With continuous damage to the cell, the injury becomes irreversible, the cell can not servieve and it dies. There are two types of cell deaths.

• Necrosis
• Apoptosis

Necrosis
When damage to the cell membrane and membranes of the organelles due to the injurious agent, enzymes leak out from the lysosomes and digest the cellular content resulting in necrosis. Also there is a inflammation in the surrounding viable tissues due to leak out of cellular content.

Common causes of necrosis

• IschemiaToxins
• Infections
• Trauma

Nuclear changes after cell death
Chromatin clumps together, therefore nuclear become shrunken, dense and darkly staining. These nuclear changes are called pyknosis. Pyknotic nucleus breaks up into small particles known as karyorrhexis. The lysosomal enzymes such as deoxyribonucleases act on these nuclear particles and lyse them and this is called karyolysis.

In rapidly occurring necrosis and in necrosis of issues with high lysosomal enzyme activity, nuclear lysis can occur without a recognizable pyknotic stage (E.g: in liquefactive necrosis).

Cytoplasmic changes after cell death
With light microscopy, cytoplasmic changes are the cellular changes detectable first in necrosis. The cytoplasm becomes deeply eosinophilic and homogeneous due to protein denaturation and loss of ribosomes (ribosomes give a basophilic tinge to the cytoplasm). Later disruption of cellular organelles leads to vacuolization of the cytoplasm. Eventually there will be a complete digestion of cellular elements by cell's own lysosomal enzymes. This is called autolysis.

Autolysis is rapid in tissues rich in hydrolytic enzymes such as pancreas, gastric mucosa. Intermediate in tissues like heart, liver and kidney, delayed in tissues containing little such enzymes like fibrous tissue. The lysosomal enzymes secreted by inflammatory cells like neutrophils in the surrounding viable tissue also aid digestion of the necrotic cells and this is called heterolysis.

Postmortem autolysis is diffuse (but starts early in organs is like pancreas) and not associated with inflammation. In necrosis, release of intracellular components initiates an inflammatory response in the surrounding viable tissues.

Apoptosis
Apoptosis is a mechanism by which cells die by activation of an inbuilt death program which is also known as programmed cell death. This is a way of cells committing suicide. This is an important mechanism by which body gets rid of unwanted cells such as aged cells, nonfunctional cells, cells with undesired actions and cells with genetic damages.

A few examples where apoptosis takes place under normal or physiological circumstances:

• During embryogenesis - shaping of organs and body parts. For example formation of fingers and toes of the fetus requires the removal, by apoptosis, of the tissues between them.
• In germinal centers of lymphoid follicles unwanted transformed immune cells are deleted by apoptosis.
• Hormone induced cell atrophy - involution of mammary tissue after cessation of breast-feeding and after menopause.
• The sloughing off of the inner lining of the uterus (the endometrium) at the start of menstruation occurs by apoptosis.
• Getting rid of cells with genetic damage and cells with harmful spontaneous mutations during the cell division.

Inappropriate apoptosis is responsible for many disease conditions.

Mechanism of apoptosis
Every cell in the body has an inbuilt death program. This program is tightly regulated and is in an inhibited state under the normal circumstances. Once this program is activated it leads to activation of cascade of events eventually leading to death of the cell.

Morphological changes during apoptosis
Initially the cytoplasm becomes deeply eosinophilic and cell becomes round or oval shaped. The organelles tightly packed together. Chromatin condensation can be seen in the nucleus. These changes leads to cell shrinkage. Then the cytoskeleton degenerates and nuclear fragmentation can be seen. The cell forms membrane bound buds which contain cytoplasm, organelles and nuclear fragments and the process called budding. These buds get pinched off from the cell and get engulfed by the neighboring cells or macrophages and degraded within phagolysosomes of these cells.

Apoptosis vs necrosis
Throughout the process of apoptosis the cell membrane is intact and there is no leakage of cellular contents to the surrounding viable tissues. Therefore there is no accompanying inflammation in apoptosis. Therefore apoptosis is a silent process with no or minimal secondary consequences in normal physiological state. This is an energy dependent process. Whereas in necrosis there is cellular swelling and disintegration of cell membrane leading to leakage of cellular contents out of the cell which triggers inflammatory response in adjacent viable tissues. Necrosis is not an energy dependent process. Necrosis is always a pathological event and do not occur in normal health.

In lymph nodes macrophages that engulf and digest apoptotic cells are called tingible body macrophages and are frequently found within the reactivate germinal centers of lymphoid follicles. The tingible bodies are the bits of nuclear debris from the apoptotic cells.