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Apoptosis

Diagrammatic Representation‎ of Apoptosis

A pathway of cell death induced by a tightly regulated suicide program. Cells destined to die activate proteins whose job it is to degrade:

  • The cell’s own nuclear DNA
  • Nuclear and cytoplasmic proteins

Apoptotic cells break up into fragments (apoptotic bodies) that contain portions of the cytoplasm and nucleus. Markers on the membrane of apoptotic bodies make them “tasty” for phagocytes (neutrophils and macrophages). However, membrane integrity is not lost (unlike necrosis). The dead cell and its fragments are phagocytosed quickly, before its contents are leaked out. Hence, apoptosis does not induce an inflammatory response in the host. [NB: Necrosis is characterised by 1) loss of membrane integrity 2) enzymatic digestion of cells 3) leakage of cellular contents and 4) a host reaction – inflammation.]

Causes of apoptosis

Physiological

This is the process to remove unwanted, aged or potentially harmful cells. Death by apoptosis is a normal phenomenon to eliminate cells that are no longer needed and to maintain a steady number of various cell populations in tissues.

  • Programmed cell destruction in embryogenesis
    • Implantation
    • Organogenesis
    • Developmental involution
    • Metamorphosis
  • Involution of hormone-dependent tissues upon hormone withdrawal
    • Endometrial breakdown during menstrual cycle
    • Ovarian follicular atresia in menopause
    • Regression of lactating breast after weaning
    • Prostatic atrophy after castration
  • Cell loss in proliferating cell populations – to maintain a constant number (homeostasis
    • Immature lymphocytes in bone marrow and thymus that don’t express useful antigen receptors
    • B lymphocytes in germinal centres
    • Epithelial cells in intestinal crypts
  • Elimination of self-reactive lymphocytes – to prevent reactions against one’s own tissues
  • Death of host cells that have served their useful purpose
    • Neutrophils at the end of an acute inflammatory response
    • Lymphocytes at the end of an immune response

Pathological

This form of apoptosis is where diseased cells are damaged beyond repair and are eliminated. Apoptosis eliminates cells that are injured beyond repair without causing a host reaction. This limits collateral tissue damage (friendly fire – eg by acute inflammation).

  • DNA damage.
    • Can be caused by: radiation, cytotoxic anti-cancer drugs and hypoxia (directly or via production of free radicals).
    • If the DNA cannot be repaired, the cell internally triggers apoptosis (caspase cascade).
    • Elimination of the cell is safer than risking mutation and malignancy.
    • For mild insults, these stimuli trigger apoptosis. Larger doses may cause necrosis.
  • Accumulation of misfolded proteins.
    • These can arise due to i) mutations in the genes coding for the proteins or ii) extrinsic factors like free radicals
    • Build-up of these proteins in the ER causes ER stress, which leads to apoptosis.
  • Cell death in certain infections.
    • Particularly in viral infections where loss of infected cells is mainly by apoptosis that is i) induced by the virus or ii) induced by the host immune response
    • An example of ii) is the action of cytotoxic T cells against a) virally infected cells, b) tumour cells and c) transplants (rejection).
  • Pathological atrophy in parenchymal organs after duct obstruction.
    • Occurs in the pancreas, parotid gland and kidney.

Morphological changes in apoptosis

  • Cell shrinkage. The cell is smaller in size. The cytoplasm is dense. The organelles are relatively normal but are more tightly packed. (In other forms of cell injury, an early feature is cellular swelling, not cell shrinkage).
  • Chromatin condensation. The chromatin aggregates peripherally, under the nuclear membrane into dense masses of various shapes and sizes. The nucleus itself may break up, producing two or more fragments.
  • Formation of cytoplasmic blebs and apoptotic bodies. The apoptotic cell first shows surface blebbing, then undergoes fragmentation into membrane-bound apoptotic bodies. The bodies contain cytoplasm and tightly-packed organelles, with or without nuclear fragments.
  • Phagocytosis of the apoptotic cells or cell bodies, usually by macrophages.
  • H&E shows the apoptotic cell as a round or oval mass of intensely eosinophilic (pink/red) cytoplasm with fragments of dense nuclear chromatin. Apoptosis can be difficult to detect histologically because 1) the products are rapidly phagocytosed and 2) apoptosis doesn’t induce inflammation.
  • NOTE: chromatin condensation is the most characteristic feature of apoptosis.

Autophagy

  • Autophagy is a process in which a cell eats its own contents.
  • It is a survival mechanism in times of nutrient deprivation.
  • Organelles and portions of cytosol are collected from the cytoplasm into an autophagic vacuole.
  • This fuses with lysosomes to form an autophagolysosome.
  • The components are digested by lysosomal enzymes.
  • It has been suggested as a separate mechanism for cell death, but this is uncertain. Cell loss in certain diseases (e.g. degenerative disease of the nervous system and muscle) is caused by autophagy.

Intracellular accumulations

  • Intracellular accumulations are one manifestation of metabolic derangements in cells.
  • There are two categories of accumulated substances:
  1. Normal cellular constituents. E.g. water, lipids, proteins and carbohydrates that accumulate in excess.
  2. Abnormal substances. They may be exogenous (e.g. minerals or products of infectious agents) or endogenous (e.g. a product of abnormal synthesis or metabolism).
  • They may accumulate transiently or permanently. They may be harmless but on occasion they are toxic. They may be in the cytoplasm (frequently inside phagolysosomes) or the nucleus.
  • Most accumulations are attributable to four types of abnormalities:
  1. A normal endogenous substance is produced at a normal or increased rate, but the rate of metabolism is inadequate to remove it. Eg: fatty change of the liver. Reabsorption protein droplets in the tubules of the kidneys.
  2. An abnormal endogenous substance, typically the product of a mutated gene, accumulates because of defects in protein folding and transport and an inability to degrade the abnormal protein efficiently. Eg: the accumulation of mutated alpha1-antitrypsin in the liver cells.
  3. A normal endogenous substance accumulates because of defects (usually inherited) in enzymes that are required for the metabolism of the substance. E.g. genetic defects in enzymes involved in the metabolism of lipid and carbohydrate, resulting in intracellular deposition of these substances, largely in lysosomes.
  4. An abnormal exogenous substance is deposited and accumulates because the cell has neither the enzymatic machinery to degrade the substance nor the ability to transport it to other sites. Eg: accumulation of carbon particles and silica.
  • The following things may accumulate in cells:
    • Lipids. This can lead to Stetosis or 'fatty'change. This is the abnormal accumulation of triglycerides in parenchymal cells (e.g. liver hepatocytes, kidney nephrons). Fatty change is most common in the liver because it is the main organ involved in fat metabolism. It also occurs in the heart, muscle and kidney.Causes include: toxins, protein malnutrition, diabetes mellitus, obesity and hypoxia. In developed nations, the most common causes of fatty liver are alcohol abuse and non-alcoholic fatty liver disease, which is often associated with diabetes and obesity. Several types of lipids can accumulate:
      • Triglycerides.
      • Cholesterol/cholesterol esters.
      • Phospholipids.
    • Cholesterol and cholesterol esters. Cellular metabolism of cholesterol is tightly regulated. Thus most cells use cholesterol for the synthesis of cell membranes without intracellular accumulations. Several pathological processes can cause accumulations in the form of intracellular vacuoles:
      1. Atherosclerosis. Smooth muscle cells and macrophages within the intimal layer of the aorta and large arteries are filled with lipid vacuoles, most of which are made up of cholesterol or its esters. These cells appear foamy. This produces the cholesterol-laden atheromas (degeneration of the walls of the arteries caused by accumulated fatty deposits and scar tissue, and leading to restriction of the circulation and a risk of thrombosis). The fat-laden cells may rupture, releasing lipids into the extracellular space.
      2. Xanthomas. Tumorous masses of foam cells. Caused by intracellular accumulation of cholesterol in macrophages occuring in hereditary hyperlipidemic states. Occurs in subepithelial c.t. in of the skin and tendons.
      3. Cholesterolosis. Focal accumulations of cholesterol-laden macrophages in the lamina propria of the gallbladder. Unknown mechanism.
      4. Niemann-Pick disease, type C. A lysosomal storage disease. Caused by mutations affecting an enzyme involved in cholesterol trafficking. Causes cholesterol build-up in several organs.
    • Proteins. Intracellular accumulations of proteins usually appear as rounded, eosinophilic droplets/vacuoles/aggregates in the cytoplasm. There are diverse causes:
      1. Reabsorption droplets in proximal renal tubules. Associated with renal diseases causing protein loss in the urine (proteinuria). Protein appears as pink hyaline droplets within the cytoplasm of the tubular cell. Reversible (protein droplets are metabolised if proteinuria stops).
      2. Normal secreted proteins may be produced in excessive amounts. ER becomes distended and forms large, homogeneous eosinophilic inclusions.
      3. Defective intracellular transport and secretion of critical proteins. Mutations in the protein can cause them to be slowly folded. Thus partially-completed proteins build up in the ER of cells and are not secreted.
      4. Accumulation of cytoskeletal proteins. Type of cytoskeleton proteins -- microtubules, thin actin filaments, thick myosin filaments and intermediate filaments. Intermediate filaments include keratin (epithelial), neurofilaments (neurons), desmin filaments (muscle cells) and glial filaments (astrocytes). Accumulation of keratin filaments occurs in alcoholic liver disease. Neurofilament accumulation occurs in the brain in Alzheimer disease. They are associated with certain types of cell injury.
      5. Aggregation of abnormal proteins. Abnormal or misfolded proteins may deposit in tissues and interfere with normal functions.
    • Hyaline change. Hyaline” refers to an alteration within cells or in the extracellular space that gives a homogeneous, glassy, pink appearance in H&E stains. It is a descriptive histological term, not a specific marker of cell injury. Examples of intracellular hyaline include intracellular accumulations of protein (reabsorption droplets, Russel bodies, alcoholic hyaline. Extracellular hyaline can occur as collagenous fibrous tissue in old scars (the biochemical basis of these scars is not clear). Long-standing hypertension and diabetes mellitus can cause the walls of arterioles (esp. in the kidney) to become hyalinised. This is due to extravasated plasma protein and deposition of basement membrane material.
    • Glycogen. Glycogen is a readily available energy source stored in the cytoplasm of healthy cells. Intracellular accumulation of glycogen can occur with an abnormality in either glucose or glycogen metabolism. They appear as clear vacuoles within the cytoplasm. Eg diabetes mellitus – glycogen is found in renal tubular epithelial cells, liver cells, beta cells of the pancreas and cells of the heart muscle.
    • Pigments. Normal (eg melanin) or abnormal pigments accumulate in cells only under special circumstances.