Cell Injury & Death Flashcards
What does a cell need to do to be able to survive?
A living cell must maintain the ability to produce energy
Must be able to adapt to adverse environmental conditions like temp, solute concentrations, oxygen supply, presence of noxious agents, infections, external signals, etc.
How does cell injury result?
Cells are stressed so severely that they can no longer adapt
OR
Cells are exposed to damaging agents and suffer from abnormal changes within
What does cell response to injury depend on?
Dose, duration, and type of injury
What do the consequence of cell injury depend on?
Depend on the type of cell - labile, stable, permanent
And ability of the cell to adapt and respond to the injury
What are the two forms of cell injury?
Reversible and Irreversible (progresses to cell death)
What is the difference between labile, stable, and permanent cells?
Labile cells - always divide (skin, GI tract, bone marrow)
Stable cells - not always dividing, needs signals (like fibroblasts and smooth muscle cells)
Permanent cells - do not divide like cardiac, nerve, and stem cells
What is the path of a cell if it undergoes a reversible injury?
Normal cell experiences stress and adapts or can’t adapt and has now a cell injury
Normal cell experiences injurious stimulus and has a cell injury
If the cell injury is mild, the cell will repair itself and return to normal
What is the path of a cell if it undergoes a irreversible injury?
A cell will experience high stress or an injurious stimulus and have severe or progressive cell injury
The cell injury then is irreversible and progresses to either necrosis or apoptosis
What are the major causes of cell injury?
Hypoxia - lack of oxygen
Physical agents and trauma
Chemical agents and drugs
Infectious agents
Immunologic reactions
Genetic defect
Nutritional imbalances (deficiencies and excesses)
What cellular compartments are damaged with cell injury?
Aerobic respiration - mitochondrial oxidative phosphorylation and ATP production
Integrity of cell membranes
Protein synthesis
Cytoskeleton
Genetic apparatus
What are the 3 main impacts on a cell after an injurious stimulus?
Membrane Damage
Protein/Cytoskeletal Damage
DNA Damage
What are the 5 major biochemical mechanisms of cell injury?
- Influx of calcium into the cell and loss of calcium homeostasis
- Mitochondrial damage
- Depletion of ATP
- Accumulation of oxygen-derived free radicals (oxidative stress)
- Defects in membrane permeability
What occurs to the cell when there is an increase in intracellular calcium?
Increase mitochondrial permeability which decreases ATP
Activation of cellular enzymes:
- Phospholipase decrease phospholipids (membrane damage)
- Protease disrupts membrane and cytoskeletal proteins (membrane damage)
- endonuclease (nuclear damage)
- ATPase decreases ATP
What causes mitochondrial injury?
Increase calcium in cytosol - decrease ATP
Oxidative stress
Breakdown of phospholipids - phospholipase A2 and sphingomyelin pathways may break down lipids. These lipid breakdown products, free fatty acids and ceramide, can damage mitochondria
How does the mitochondrial membrane being damaged affected ATP production?
Potential of inner and outer layers of mitochondrial membrane help make ATP
So if it is damaged, action potential is not generated and ATP is not made
How does decreased oxygen supply, toxins, and radiation impact the mitochondria and then the cell?
They lead to mitochondrial damage or dysfunction which decreases ATP generation and increases production of ROS
This then leads to multiple cell abnormalities and necrosis
How does decreased survival signals and DNA and protein damage impact the mitochondria and then the cell?
Increase in pro-apoptotic protein and decrease in anti-apoptotic proteins
Causes mitochondria to leak proteins like cytochrome c
cytochrome c then triggers apoptosis within cell
Explain the mechanisms of the depletion of ATP and how that causes cell injury.
Depletion of ATP and lack of ATP synthesis are frequently caused by chemical injury as well as hypoxia
When oxidative phosphorylation cannot proceed because of lack of oxygen or interference with phosphorylation path, the levels of ATP in the cell decrease
How does ischemia lead to depletion of ATP and then MPD (membrane, protein, DNA damage)?
Ischemia causes hypoxia or a lack of oxygen.
Lack of oxygen causes the mitochondria to decrease its process of oxidative phosphorylation, which leads to a decrease in ATP
A decrease in ATP means sodium pump activity decreases and can’t pump out sodium so intracellular calcium, water, and sodium increases. The efflux of potassium increases as well. This causes the ER and cell to swell and lose microvilli, and create blebs (M)
Decrease in ATP means to cell transitions to anaerobic glycolysis which increases lactic acid and decreases glycogen and pH. The acidic pH causes nuclear chromatin to clump. (D)
A decrease in ATP also causes detachment of ribosomes which leads to decreased protein synthesis
What does decreased ATP lead to? 4x
- No energy for Sodium Potassium pump leads to cellular and organelle swelling (osmotic gradient altered)
- No energy for calcium pump - increase intracellular calcium that activate enzymes that causes membrane damage
- Increase anaerobic glycolysis - decrease pH and cause chromatin clumping (DNA damage)
- Detached ribosomes - monosomes decrease protein synthesis so we lose housekeeping proteins
Explain the mechanism of oxidative stress in regards to cell injury.
Normal metabolism results in formation of oxygen derived free radicals BUT these free radicals are highly reactive and form double bonds quickly and non-specifically
These bonds alter the structure of proteins, nucleic acids, and lipids
If cells have more damage than can be prevented or repaired by usual cell mechanisms then free radical damage can occur and accumulate
What is oxidative stress?
Accumulation of damaged caused by oxygen derived free radicals
What can cause increases in ROS? Why?
Oxygen therapy - excess oxygen
PMNs, macrophages - inflammation
PMNs, xanthine oxidase - reperfusion injury after ischemia
Mixed function oxidation, cyclic redox reactions - chemical toxicity
radiotherapy - ionizing radiation
Mutagens - chemical carcinogenesis
Mitochondrial metabolism - Biological aging
What are examples of ROS that can build up? How do they cause injury?
O2- (superoxide)
.OH (hydroxyl radical)
ONOO (peroxynitrite)
lipid peroxide radicals
Cause membrane damage
