HC10: Repair mechanism

Apoptosis

Apoptosis is a pathway of cell death that is induced by a tightly regulated suicide program. This can be:

• Physiologic: pre-programmed
• Pathologic: associated with necrosis

Morphology:

Apoptosis has the following characteristics:

• Decrease in cell size
  • Shrinkage
• Increase in chromatin concentration
  • Hyperchromasia: the nucleus becomes small and dark
  • Pyknosis → karyohexis → karyolysis
    • Pyknosis = shrinkage
    • Karyohexis/karyolysis = nuclear fragmentation
• Increase in membrane blebs

This is a very organized process → parts are recycled for the body to reuse. Apoptosis always results in phagocytosis, which is done by macrophages.

Biochemistry:

During apoptosis, the following processes take place:

1. Protein digestion
   • This is done by a family of caspases that ensure that the pre-programmed suicide happens in an organized way
     • A family of enzymes
2. DNA-breakdown
3. Phagocytic recognition

There are several subcellular responses to caspase activation:

• Lysosomal response → auto-digestion
• Smooth endoplasmic reticulum (SER) activation
• Mitochondrial swelling
• Cytoskeleton breakdown
  • Thin filaments
    • Actin, myosin
  • Microtubules
  • Intermediate filaments
    • Keratin, desmin, vimentin, neurofilaments, glial filaments

Necrosis

Necrosis isn't programmed and is much faster than apoptosis. It occurs when there is an immediate irreversible, progressive injury. There isn't any time for a nicely orchestrated process:

• A lot of fluid leaves the cell
• Neutrophils are attracted to the cell → inflammatory response
• Macrophages travel to the cell after a while

Necrosis versus apoptosis:

It is important to differentiate between necrosis and apoptosis:

• Apoptosis: normal death/replacements
  • Shrinkage → reduced cell size
  • Fragmented nucleus
  • Intact plasma membrane
  • Cellular content may be intact
  • No adjacent inflammation
  • Often physiologic
• Necrosis: premature death due to causes
  • Swelling → enlarged cell size
  • Karyolysed nucleus
  • Disrupted plasma membrane
  • Enzymatic digestion of cellular content
  • Frequent adjacent inflammation
  • Invariably pathologic

Clinical perspectives

Graft versus Host disease:

The pathway of apoptosis is activated in graft versus host disease. This is cytotoxic T-lymphocyte-mediated apoptosis

Dysregulated apoptosis:

Apoptosis is also activated in cancer. P53 can signal that there is too much injury in DNA and apoptosis is triggered. If P53 is mutated, the apoptosis-process is disregulated and damaged DNA will not result in apoptosis → cancer will progress.

Endometrial cancer:

In a case of endometrial cancer, grade 1 and stage I, the following is visible:

• Complex hyperplasia → atypical proliferation of epithelial cells with partly solid growth
• Squamous metaplasia → the tumor should be classified as endometrioid
• Large areas with necrosis in the center of the atypical proliferation
• Hypertrophic myometrial smooth muscle cells in the surrounding myometrium
• Atrophic ovaries
• Focal tubal metaplasia in the cervix

Ischemia and hypoxia:

Ischemia and hypoxia both cause cell injury. In both cases, there is a reduced oxygen availability. Ischemia is more damaging because there isn't any blood supply at all, which also will lead to nutrients deficiency.

Intracellular accumulations

Due to metabolic scenarios of cellular stress that comes from inside the body, accumulations of proteins and other particles can occur. These are known as intracellular accumulations, which can be caused by:

• Abnormal metabolism
  • For example lipids → obesity
• Defects in protein folding or transport
  • For example amyloid → Alzheimer
• Lack of lysosomal function
  • For example endogenous accumulations
• Ingestion of indigestible materials
  • For example exogenous and endogenous material

Exogenous and endogenous material:

Exogenous and endogenous material can also cause a cellular accumulation response:

• Exogenous: for example tattoos or antracosis
• Endogenous: golden-yellowish-brown stains caused by hemosiderin, melanin, lipofucsin or bile

Cellular aging

Cellular aging consists of 2 processes:

• Programmed theory (80%)
• Wear and tear theory (20%)

Werner syndrome:

Werner syndrome is caused by a genetic mutation in all germline cells → the mutation is spread throughout the entire body. People with Werner syndrome age too quickly.

Multifactorial:

Aging is a multifactorial process that consists of:

• Telomere shortening → replicative senescence
• Environmental insults → free radicals → DNA damage and damage of proteins and organelles
• DNA-repair defects → DNA damage → accumulation of mutations
• Abnormal growth factor signaling → unknown mechanism
  • Possibly caused by calorie restriction

Telomerase:

The ends of DNA are named telomeres. When cells divide, they copy their DNA. Every time this happens, the telomere becomes shorter. When the telomere reaches a certain length, the cell will go into apoptosis.

In a few scenarios, the cell can lengthen the telomere with help of the enzyme telomerase. This only occurs in germ cells, stem cells and some cancer cells.