• Information
  1. Apotosis Versus Necrosis
  2. Mechanisms of Apoptosis
  3. Normal Physiological Apoptosis
  4. Apoptosis in Disease

A. Apotosis Versus Necrosis

1. Characteristics of Apoptosis
   1. Programmed cell death (PCD) pathways
   2. Occur in both physiologic and pathologic settings
   3. Requires energy (ATP)
   4. DNA breakdown comprised of specific size fragments (multiples of 185 base pairs)
   5. Plasma membrane is intact, blebbed, with molecular changes
   6. Inflammation does not occur
   7. In multicellular organisms, cells underoing apoptosis make a commitment to die
2. Characteristics of Necrosis
   1. Usually due to acute ischemia, traumatic injury, certain toxins
   2. Severe ATP depletion due to ischemia is most common
   3. Necrosis is abnormal tissue death, does not require ATP
   4. DNA is broken down into randomly sized fragments
   5. Cellular swelling, disruption of organelles, death of patches of tissue
   6. Plama membrane lysed; cell contents strewn out
   7. Necrosis is nearly always focal and stimulates strong inflammatory response
   8. Cell debris is cleared by immigrant phagocytes (macrophages or macroglia in brain)
   9. Usually appears hypereosinophilic on hematoxylin-eosin (H and E) staining

B. Mechanisms of Apoptosis

1. Specific proteases catalyze final steps in apoptotic cell death
2. These proteases are cysteine-aspartyl proteases, called caspases
3. Four stages of apoptosis have been defined:
   1. Committment to death by extracellular or intracellular triggers
   2. Cell killing (execution) by activation of intracellular proteases (caspases)
   3. Engulfment of cell corpse by other cells
   4. Degradation of the cell corpse within the lysosomes of phagocytic cells
4. Caspase Cascade
   1. Various stimuli described above eventually activate the executioner (caspase) cascade
   2. At least 10 different caspases exist in human cells
   3. Caspases 8 and 9 activate the effector caspases 3, 6 and 7
   4. Caspases 3, 6 and 7 are involved in degradation of cellular and nuclear proteins
   5. Caspase 3 also activateds CAD, or caspase activated DNAse, which degrades DNAse
5. Initiating Pathways [3]
   1. Two major pathways for initiation of apoptosis exist
   2. These are the death ligand mitochondrial and pathways
   3. Cell stress directly impacting mitochondrial integrity can lead to cytochrome c release
   4. Cytochrome c release binds to Apaf-1 and this complex activates caspase 9
   5. Death ligands stimulate cytoplasmic death complexes which activate caspase 8
   6. Hypoxia, drugs, radiation (p53), and lack of survival factors work through caspase 9
   7. Fas and TNF pathways mainly use caspase 8 to trigger cell death
6. Stimuli for Apototic Cell Death in Mammals
   1. Growth factor deficiencies
   2. Ionizing radiation
   3. Free radical toxicity
   4. Death receptor activation (such as Fas or CD95 triggering)
   5. Metabolic or cell cycle perturbation

C. Normal Physiological Apoptosis

1. Immune System
   1. Developing thymocytes (T cells) undergo apoptosis in thymus
   2. B cells undergo apoptosis at immature stage if they encounter antigen
   3. Circulating lymphocytes have predetermined longevity in serum
   4. Neutrophils live for 2-3 days in circulation
2. Central and Peripheral Nervous Systems
   1. Programmed cell death of majority of neurons
   2. Making neural connections through axons probably required to prevent apoptosis
   3. Expression of anti-apoptosis gene Bcl-xL likely required for adult neuron viability
3. Tubular Structures
   1. Required for development of digits on limbs
   2. Limb digits are formed by cell death of interdigitary cells
   3. Visceral tube structures such as intestine and trachea formed by central zone cell death

D. Apoptosis in Disease

1. Lymphoproliferative Syndrome
   1. Rare genetic disorder with inactivation of Fas (CD95) gene [4]
   2. Lymphocytes fail to undergo apoptosis
   3. Result is syndrome of severe lymphadenopathy, immunodeficiency, autoimmunity
   4. Death usually due to infection
2. Cancer Syndromes
   1. Abnormal p53 genes in Li-Fraumeni Syndrome leads to reduced apoptosis
   2. These patients develop multiple different kinds of cancer at high rates
   3. Overexpression of anti-apoptotic protein Bcl-2 in follicular lymphomas
3. Neurodegenerative Diseases
   1. Likely role in many neurodegenerative diseases
   2. Alzheimer's Disease and other dimentias
   3. Parkinson's Disease
   4. Amyotrophic Lateral Sclerosis (ALS)
   5. Spinal muscular atrophy
   6. Huntington's Disease
4. Heart Disease [5]
   1. Apoptosis plays a role in progressive cardiac deterioration in failing heart [6]
   2. Idiopathic dilated cardiomyopathy may be due to abnormal myocyte apoptosis
   3. Apoptosis also found in arrhythmogenic right ventricular dysplasia [7]
   4. Ischemic necrotic cell death in myocardial infarction surrounded by apoptotic zone
5. Stroke
   1. Necrotic cell death occurs in central ischemic zone
   2. Neurons surrounding central ischemic zone undergo apoptosis ("penumbra region")
6. Deficient Apoptosis (Acquired)
   1. Graves' Disease and Hashimoto's thyroiditis
   2. Hypereosinophilia Syndomre
   3. Systemic Lupus Erythematosus [8]
   4. Type I Diabetes Mellitus
   5. Osteoporosis (osteoclast apoptosis failure)
7. Excessive Apoptosis
   1. Ischemic diseases - MI, stroke, as above
   2. Degenerative neurologic diseases (as above)
   3. Aplastic Anemia
   4. AIDS
   5. Liver Failure
   6. Multiple Sclerosis
   7. Myelodysplastic syndrome
   8. Ulcerative colitis
   9. Chronic neutropenia
   10. Wilson's Disease
   11. Other Autoimmune disorders [8]

References

1. Friedlander RM. 2003. NEJM. 348(14):1365
2. Saikumar P, Dong Z, Mikhailov V, et al. 1999. Am J Med. 107(5):489
3. Rust C and Gores GJ. 2000. Am J Med. 108(7):567
4. Drappa J, Vaishnaw AK, Sullivan KE, et al. 1996. NEJM. 335:1643
5. James TN. 1999. Am J Med. 107(6):606
6. Olivetti G, Abbi R, Quaini F, et al. 1997. NEJM. 336(16):1131
7. Mallat A, Tedgui A, Fontaliran F, et al. 1996. NEJM. 335:1190
8. Grodzicky T and Elkon KB. 2000. Am J Med. 108(1):73