MODES OF CELL DEATH


EM Cabana, DVM (CLSU, Phil '84), MVSt (UQ, Aus '91)
Asst Professor - Veterinary Pathology
College of Veterinary Science and Medicine
Central Luzon State University
Nueva Ecija 3120, Philippines
http://www2.mozcom.com/~emcdvm



CELL DEATH

Death of cells in the animal body may either occur normally of pathologically. Three distinct modes of cell death are recognised and include Necrobiosis, Apoptosis, and Necrosis. The former two processes are considered part of the normal homeostatic mechanism of the body in regulating cell population, renewal of cells, and in "fine tuning" of organs. As cells continually die even in clinically normal animals, these may be hastened in events of disease processes.

NECROBIOSIS

Necrobiosis is programmed cell death, and involves individual or groups of cells upon reaching their life span. The process occurs virtually unnoticed, with the dead cells replaced by the same cell type following cell reproduction (mitosis and meiosis). Necrobiosis occurs without pathologic sequel because cell function is not interrupted.

 Necrobiosis occurs in adults as part of normal cell turnover. An example is red blood cell turnover. The process starts when their haemoglobin molecules begin to precipitate and new haemoglobin cannot be synthesised. Then, the marrow to replace the dying red blood cells produces new red blood cells with “fresh” haemoglobin. Necrobiosis also operates in epithelial turnover in the intestines, where cells are continually produced in the crypts. It also occurs in keratinisation of the skin where cells become filled with keratin. Then, the nuclei degenerate, and the cell desquamate from the skin surface.
 

APOPTOSIS

Apoptosis is a form of cell death and removal involving one cell at a time. Cells programmed for removal undergo "suicidal action". It may occur normally in several processes that include the following:

1) Embryonic morphogenesis - as in  deletion of interdigital tissue  in developing chicks
2) Metamorphosis - as in deletion of  tail in a tadpole as it matures  into a frog
3) Mature tissue homeostasis - as in  remodeling of uterus after  pregnancy
4) Involution of adult tissue - as may  occur in the thymus
5) Pathological states - as in cell  death following exposure to  ionising radiation and  radiomimetic cytotoxic drugs, in  malignant neoplasms, and cell-mediated immunity.


In apoptosis, cell death involves one cell at a time, and the dead cell fragments are phagocytosed and digested by resident cells (Figure 5). Like necrobiosis, the process occurs virtually unnoticed, and no pathologic sequels occur. In the literature, several names were used in describing apoptotic fragments before the term was coined. This includes "acidophil or Councilman's bodies" in hepatitis, and "ghost cells" in some skin disorders.
 

  Figure 5. Schematic diagram of Apoptosis


NECROSIS

Necrosis is death of cells or tissues following injury. Cell degeneration may result to necrosis if the injury persists. If it is severe that adaptive responses could no longer operate, and the condition could no longer be reversed, cell death occurs. Unlike the former two modes of cell death, necrosis involves pathological processes and sequel.

Indicators of Necrosis

 Necrosis is recognised by:

1) Changes in the nucleus

 a) Swelling and clumping of   chromatin
 b) Pyknosis - condensation of   chromatin and shrinkage of   the nucleus
 c) Kayorrhexis - fragmentation   of the nucleus
 d) Karyolysis - dissolution of   the nucleus by the action   of deoxyribonuclease

2) Changes in cytoplasmic staining

 a) Positive staining with vital   dyes reflecting abnormal   membrane permeability
 b) Opacification due to   denaturation of proteins   in the cytoplasm
 c) Eosinophilia due to increased   affinity to acidic dyes

3) Ultrastructural changes in chronological order as:

 a) Margination or progressive   loss of nuclear chromatin
 b) Focal rupture of the nuclear   membrane
 c) Breakdown of plasmalemma
 d) Development of flocculent   densities in the   mitochondria

Grossly, necrotic tissue shows the following features:

1) Loss of colour or paleness of  tissue
2) Loss of strength in which the  necrotic tissue is soft and  friable
3) A distinct zone of demarcation is  often seen between necrotic and  viable tissue.

Figure 6. Schematic diagram of necrosis
Biochemical Changes

The process of necrosis involves a series of biochemical changes in cells. The first biochemical indication is the rapid fall in intracellular pH following altered oxygen metabolism in dying cells. These event leads to cessation of oxidative phosphorylation in mitochondria resulting to a further fall in pH. As a result, ATPs are depleted, and the energy dependent Sodium-Potassium pump that regulates the exchange of ions ceases to function. Potassium ions are released with a consequent influx of sodium ions raising the osmotic pressure inside the cell. This condition draws water towards the cell and results to disruption of organelles, with the consequent release of enzymes stored in the lysosomes. As a result, protein molecules undergo denaturation, and lysis of cell occurs.

At the clinical level, these biochemical changes serve as a source of information that aids in the recognition of certain diseases. The enzymes and denatured protein molecules released from dead cells and tissues find their way into the circulation which could then be identified, measured and the source tissue known. For example, enzymes such as aspartate transaminase (serum glutamic oxaloacetic transaminase or SGOT) and alanine transaminase (serum pyruvic transaminase or SGPT) released from dead liver cells suggests liver disease. The enzyme creatine kinase and denatured protein myoglobin suggest muscle disease.

Basic Types of Necrosis

Two types of necrosis are recognised and are based on the degree of preservation of the architecture of the cells and tissues. These are as follows:

Coagulative necrosis

Coagulative necrosis is characterised by the preservation of cellular and tissue architecture. Microscopically, the nucleus, cytoplasm, and cellular outlines including the arrangements of cells in the necrotic tissue are still intact. This type of necrosis is often difficult to detect grossly, except probably when the affected area is large where subtle changes in tissue colour may be recognised. It usually results from acute disease conditions such as acute toxicity (chemical toxicants or biological toxins) and sudden deprivations in blood supply.

Liquefactive or Lytic necrosis

 Rapid enzymatic dissolution of the cell that results in complete destruction is called liquefactive or lytic necrosis (or colliquative necrosis). It is seen in bacterial infections that lead to pus formation in which proteolytic enzymes are released from leucocytes. Pus is the evidence of liquefactive necrosis.


Special Forms of Necrosis

1) Fat Necrosis - occur in two forms: Traumatic Fat Necrosis result from rupture of fat cells because of trauma; Enzymic Fat Necrosis occurs following the enzymic splitting of fat into fatty acid and glycerol by action of lipases (seen in pancreatitis).

2) Zenker Necrosis (Zenker degeneration) - loss of striations in muscles following necrosis (a type of coagulative necrosis in striated muscles).

3) Caseation Necrosis - the presence of friable, cheesy or pasty, amorphous material in necrotic area, usually reserved but not limited to those seen in tuberculous lesions.

4) Fibrinoid Necrosis - a special form of necrosis associated with the accumulation of fibrinoid (see protein overload) in connective tissues and blood vessel walls.

5) Gangrenous Necrosis - necrosis of tissue following deprivation of blood supply, and putrefaction following invasion by saprophytic bacteria. If it is moist, it is called Wet Gangrene. If moisture is not present, it is called Dry Gangrene.

6) Infarct - a form of coagulative necrosis resulting from a sudden deprivation of blood supply (process: infarction, see under haemodynamic changes)

Other Terms Used in Association with Necrosis

1) Malacia - an area of liquefactive necrosis of the nervous tissues. Literally mean "softening"

2) Slough - a piece of necrotic tissue separating from viable tissue. Applied to necrosis of surface epithelia.

3) Ulcer - shallow area of necrosis, applied to epithelial surfaces.

4) Sequestrum - an isolated area of necrosis warded off from viable tissue. Applied to isolated necrosis of bones.
 

Tissue Reactions to Necrosis

Dead cells and tissues are recognised as foreign and incite tissue reactions. Necrotic tissue may be walled off by proliferating fibrous tissue, incite inflammatory reactions leading to phagocytosis of the necrotic debris, liquefied and drained and the tissue repaired.

The effects of necrosis upon the host vary depending on the type of cells involved, the location of the tissue involved, the number of cells affected, and the rate at which cells are affected.  The location and type of cells involved is critical. To illustrate this point, focal necrosis of the liver such as the necrotic tracts caused by migrating nematode larvae may not affect the animal as a whole. In contrast, infarction of the heart may prove fatal to the animal. Similarly, necrosis of neurons would surely cause interference in normal body functions. The rate and number of cells affected also have some bearing on the outcome of necrosis. Slow involvement of cells and tissues may be countered by the process of healing, while rapid death of cells following severe intoxication will produce death in a matter of days. Thus, areas of necrosis encountered during necropsy examinations should be evaluated for its possible significance in the disease process.