Cell injury and death - apoptosis and necrosis Flashcards
Describe the mechanisms of cellular injury
- Physical trauma
- Metabolic interruption e.g. accumulation of protein
- DNA damage e.g. via cytotoxicity, p53
- Failure of membrane integrity e.g. via MAC, bacterial toxins, protein pump failure
Describe the morphology of cellular injury
- ER and mitochondrial swelling
- Loss of ribosomes
- Nucleolus degradation
- Membrane blebbling
- Lysosomal rupturing
- May be sub-lethal, with cellular recovery seen.
Describe the morphology of cellular injury
- 2 main processes
1.) Swelling (hydropic change, oncosis)
Cytoplasm becomes swollen due to osmotic movements as water potential is decreased - a result of decreased sodium movement.
Follows changes to metabolism as no ATP available for ATPase activity
2.) Fatty acid change (steatosis)
Triglycerides accumulate in liver cells. Lipid globules form in the cytoplasm
–> Diabetes: Increased FA
–> Alcoholism: Disrupted lipid metabolism
Cell death through apoptosis
REGULATED. An energy dependent process which uses cellular enzymes. Sees the ‘neat’ removal of material.
*Membrane remains intact. No leakage of cellular contents.
* No associated inflammation - although secondary necrosis may follow due to neutrophil infiltration
Can follow a physiological or pathological trigger!
- Apoptotic bodies form.
Cell death through necrosis
- A continuation of reversible injury
- Cellular transporters, e.g. ATPase, fail - due to lack of cellular energy. Na accumulation leads to osmosis and cellular swelling.
- Organelle and cell membrane breakdown is seen.
- Autolysis occurs due to lysosomal membrane leakage.
- Cellular contents and enzymes are released, leading to inflammation
Physiological and pathological triggers of apoptosis
Physiological: Embryological development e.g. digit formation, involution of hormone dependent tissues e.g. uterus, elimination of unwanted cells e.g. neutrophils
Pathological: DNA damage, misfolded proteins, apoptosis of lymphocytes directed against pathogens
Describe the different patterns of necrosis
Coagulative - In most tissues, apart from the brain
Caseous - In the lungs
Liquefying - In the brain
Define ischaemia and infarction
Ischaemia: Decreased perfusion of blood to tissues leading to decreased nutrient availability, such as oxygen. A lack of oxygen prevents oxidative phosphorylation from proceeding, ATP production is then reduced. This leads to changes in membrane permeability and membrane breakdown. Reactive oxygen species build up and waste products (lactic acid) as the cell is forced towards anaerobic respiration.
Infarction: The death of tissues due to ischaemia
Factors governing the susceptibility of organs to infarction
- Blood supply: Watershed areas are of greater susceptibility
- Nerve cells and cardiac cells are more susceptible due to increased metabolic demand
- Organs which are able to divide will repair (such as liver) however those which cannot will repair by fibrosis.
Intrinsic activation of apoptosis
Occurs via Bcl-2 family proteins.
- Bax and Bak are pro-apoptotic proteins. They act by increasing mitochondrial permeability. Cytochrome C is released which then causes increased calcium concentration. This induces the activity of caspases.
- Bcl-2 and Bcl-xl: Anti-apoptotic proteins
Extrinsic activation of apoptosis
Occurs via FasR (on the surface of epithelial cells) and FasL (on T cells). Leads to apoptosis of cells.
Reperfusion injury
Tissue damage can be seen following reperfusion.
This occurs as free radicals are generated during ischaemic periods. When blood flow is restored these free radicals are converted to reactive oxygen species. Tissue damage, due to inflammation, may occur due to increased numbers of immune cells.
Thrombus formation
A solid mass of blood constituents formed within the vascular system.
3 pre-disposing situations:
-Changes in the internal surface of the vessel
- Changes in blood flow
- Changes in blood constituents
Describe the changes in membrane transporters in necrosis and in ischaemia
Necrosis: The cell membrane is damaged, increasing permeability to Na+. This disrupts the function of the Na/K ATPase as the membrane potential is lost. This decreases the availability of ATP
Ischaemia: Due to insufficient oxygen supply ATP cannot be synthesised. This leads to dysfunction of the ATP dependent Na+/K+ transporter, leading to cell death - as the membrane potential is lost. Cell contents then ‘leak’. ROS may also damage the cell membrane.
