Cell death occurs by two distinct processes:

  1. Apoptosis
  2. Necrosis.

    Apoptosis

    Apoptosis is defined as the natural or programmed death of the cell under genetic control. Originally, apoptosis refers to the process by which the leaves fall from trees in autumn (In Greek, apoptosis means ‘falling leaves’). It is also called ‘cell suicide’ since the genes of the cell play a major role in the death.

     

    This type of programmed cell death is a normal phenomenon and it is essential for normal development of the body. In contrast to necrosis, apoptosis usually does not produce inflammatory reactions in the neighboring tissues.

    Functional Significance of Apoptosis

    The purpose of apoptosis is to remove unwanted cells without causing any stress or damage to the neighboring cells. The functional significance of apoptosis:

  3. Plays a vital role in cellular homeostasis. About 10 million cells are produced every day in the human body by mitosis. An equal number of cells die by apoptosis. This helps in cellular homeostasis
  4. Useful for removal of a cell that is damaged beyond repair by a virus or a toxin
  5. An essential event during the development and in the adult stage.

    Examples:

  6. A large number of neurons are produced during the development of the central nervous system. But up to 50% of the neurons are removed by apoptosis during the formation of synapses between neurons
  7. Apoptosis is responsible for the removal of tissues of webs between fingers and toes during developmental stage in fetus
  8. It is necessary for regression and disappearance of duct systems during sex differentiation in the fetus.
  9. The cell that loses the contact with neighboring cells or basal lamina in the epithelial tissue dies by apoptosis. This is essential for the death of old enterocytes that shed into the lumen of intestinal glands.
  10. It plays an important role in the cyclic sloughing of the inner layer of the endometrium, resulting in menstruation.
  11. Apoptosis removes the autoaggressive T cells and prevents autoimmune diseases.

    Activation of Apoptosis

    Apoptosis is activated by either withdrawal of positive signals (survival factors) or the arrival of negative signals.

    Withdrawal of positive signals

    Positive signals are the signals which are necessary for the long-time survival of most of the cells. The positive signals are continuously produced by other cells or some chemical stimulants. Best examples of chemical stimulants are:

  12. Nerve growth factors (for neurons)
  13. Interleukin-2 (for cells like lymphocytes).

    The absence or withdrawal of the positive signals activates apoptosis.

    Arrival of negative signals

    Negative signals are the external or internal stimuli which initiate apoptosis. The negative signals are produced during various events like:

  14. Normal developmental procedures
  15. Cellular stress
  16. Increase in the concentration of intracellular oxidants
  17. Viral infection
  18. Damage to DNA
  19. Exposure to agents like chemotherapeutic drugs, X-rays, ultraviolet rays and the death receptor ligands.

    Death receptor ligands and death receptors

    Death receptor ligands are the substances which bind to specific cell membrane receptors and initiate the process of apoptosis. The common death receptor ligands are tumor necrosis factors (TNF- a, TNF- p) and Fas ligand (which binds to the receptor called Fas).

    Death receptors are the cell membrane receptors which receive the death receptor ligands. Well-characterized death receptors are TNF receptor-1 (TNFR1) and TNF-related apoptosis-inducing ligand (TRAIL) receptors called DR4 and DR5.

    Role of mitochondria in apoptosis

    External or internal stimuli initiate apoptosis by activating the proteases called caspases (cysteinyl-dependent aspartate-specific proteases). Normally, caspases are suppressed by the inhibitor protein called apoptosis inhibiting factor (AIF).

    When the cells receive the apoptotic stimulus, mitochondria releases two protein materials. First one is Cytochrome C and the second protein is called second mitochondria-derived activator of caspases (SMAC) or its homologue diablo.

    SMAC/diablo inactivates AIF so that the inhibitor is inhibited. During this process, SMAC/diablo and AIF aggregate to form apoptosome which activates caspases. Cytochrome C also facilitates caspase activation.

    Apoptotic Process

    Cell shows the sequence of characteristic morphological changes during apoptosis, viz.:

  20. Activated caspases digest the proteins of cyto- skeleton and the cell shrinks and become round
  21. Because of shrinkage, the cell loses the contact with neighboring cells or surrounding matrix
  22. Chromatin in the nucleus undergoes degradation and condensation
  23. Nuclear membrane becomes discontinuous and the DNA inside nucleus is cleaved into small fragments
  24. Following the degradation of DNA, the nucleus breaks into many discrete nucleosomal units, which are also called chromatin bodies
  25. Cell membrane breaks and shows bubbled appearance
  26. Finally, the cell breaks into several fragments containing intracellular materials including chromatin bodies and organelles of the cell. Such cellular fragments are called vesicles or apoptotic bodies
  27. Apoptotic bodies are engulfed by phagocytes and dendritic cells.

    Abnormal Apoptosis

    Apoptosis within normal limits is beneficial for the body. However, too much or too little apoptosis leads to abnormal conditions.

    Common abnormalities due to too much apoptosis:

  28. Ischemic-related injuries
  29. Autoimmune diseases like:
  30. Hemolytic anemia
  31. Thrombocytopenia
  32. Acquired immunodeficiency syndrome (AIDS)
  33. Neurodegenerative diseases like Alzheimer’s disease.

    Common abnormalities due to too little apoptosis:

  34. Cancer
  35. Autoimmune lymphoproliferative syndrome (ALPS).

    Necrosis

    Necrosis (means ‘dead’ in Greek) is the uncontrolled and unprogrammed death of cells due to unexpected and accidental damage. It is also called ‘cell murder’ because the cell is killed by extracellular or external events. After necrosis, the harmful chemical substances released from the dead cells cause damage and inflammation of neighboring tissues.

    Causes For Necrosis

    Common causes of necrosis are injury, infection, inflammation, infarction and cancer. Necrosis is induced by both physical and chemical events such as heat, radiation, trauma, hypoxia due to lack of blood flow and exposure to toxins.

    Necrotic Process

    Necrosis results in lethal disruption of cell structure and activity. The cell undergoes a series of characteristic changes during the necrotic process, viz.

  36. Cell swells causing damage of the cell membrane and appearance of many holes in the membrane
  37. Intracellular contents leak out into the surrounding environment
  38. Intracellular environment is altered
  39. Simultaneously, large amount of calcium ions are released by the damaged mitochondria and other organelles
  40. Presence of calcium ions drastically affects the organization and activities of proteins in the intracellular components
  41. Calcium ions also induce release of toxic materials that activate the lysosomal enzymes
  42. Lysosomal enzymes cause degradation of cellular components and the cell is totally disassembled resulting in death
  43. Products broken down from the disassembled cell are ingested by neighboring cells.

    Reaction of Neighboring Tissues After Necrosis

    Tissues surrounding the necrotic cells react to the breakdown products of the dead cells, particularly the derivatives of membrane phospholipids like the arachidonic acid. Along with other materials, arachidonic acid causes the following inflammatory reactions in the surrounding tissues:

  44. Dilatation of capillaries in the region and thereby increasing local blood flow
  45. Increase in the temperature leading to reddening of the tissues
  46. Release of histamine from these tissues which induces pain in the affected area
  47. Migration of leukocytes and macrophages from blood to the affected area because of increased capillary permeability
  48. Movement of water from blood into the tissues causing local edema
  49. Engulfing and digestion of cellular debris and foreign materials like bacteria by the leukocytes and macrophages
  50. Activation of immune system resulting in the removal of foreign materials
  51. Formation of pus by the dead leukocytes during this process
  52. Finally, tissue growth in the area and wound healing.
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