Exam #1: Cell Injury & Death Flashcards
What is cell injury?
What happens when cells stressed so severely that they can no longer adapt, or when they are exposed to damaging agents and suffer abnormal changes within.
List the major causes of cell injury.
1) Hypoxia
2) Trauma
3) Chemical agents & drugs
4) Infectious agents
5) Immunologic reactions
6) Genetic Defects
7) Nutritional imbalances
What are the three modes of hypoxia?
1) Loss of blood supply
2) Decrease in oxygen carrying capacity i.e. reduction of Hb (anemia or CO poisoning)
3) Poisoning in enzymes of ox-phos
What are the cellular compartments damaged during cell injury?
- Aerobic respiration & ATP production
- Integrity of cell membranes
- Protein synthesis
- Cytoskeleton proteins
- Genetic apparatus
What does M-P-D stand for?
Membranes
Proteins
DNA
What are the six mechanisms of cell injury?
1) ATP depletion
2) Loss of Ca++ homeostasis (i.e. Ca++ entry)
3) ROS
4) Defective membrane permeability
5) Mitochondiral damage
6) Cytoskeleton damage
Are all free radicals bad?
No–we need free radicals
How does excess Ca++ lead to cellular injury?
- Excess Ca++ ACTIVATES the following ENZYMES:
1) Phospholipase–> decreases phospholipids
2) Proteases–>disruption of membrane and cytoskeleton proteins - Both leading to membrane damage
3) Endonucleases–>nuclear damage
4) ATPase–>depletion of ATP
*Excess Ca++ also changes the mitochondiral membrane permeability and leads to a reduction in ATP production
What causes excess Ca++?
- Injurious stimuli, especially ischemia and certain toxins, initially cause the release of Ca++ from intracellular stores–SER & Mitochondria
- Later in the injury process, Ca++ influx occurs across the plasma membrane
What are the causes of mitochondiral injury?
Most things that cause injury to the cell will cause injury to the mitochondria via:
1) Increase of Ca++ in the cytosol
2) Oxidative stress
3) Lipid peroxidation
Why does mitochondrial membrane destruction lead to a decrease in ATP production?
- Mitochondrial membrane proteins pump H+ out of the mitochondira to generate a potential grandient
- The H+ that is pumped out, then comes back into the cell down its concentration gradient & provides energy for ATP synthase to convert ADP–>ATP
*****Destruction of the mitochondiral membrane prevents the H+ gradient from being generated, and consequently, prevents ATP production
What three things can lead to necrosis via mitochondrial damage or dysfunction?
Decreased oxygen
Toxins
Radiation
Why is ATP depletion bad? What are the three outcomes of ATP depletion?
Ischemia–> lack of oxygen phosphorylation–>decreased ATP, causing:
1) Without ATP, there is no energy to maintain the Na+/K+ Pump & Na+ cannot be pumped out of the cell
- Na+ increases in the cell & changes the osmotic gradient (water enters)causing swelling of the cell & organelles (blebbing)
2) Anaerobic glycolysis increases to compensate for the lack of ATP, leading to an increase in lactic acid production and a decrease in pH, which causes a “clumping” of DNA/ chromatin
3) Detachment of ribosomes & a decrease in protein synthesis
What is oxidative stress?
Accumulation of damage to the cell caused by oxygen-derived free radicals
How are ROS damaging?
- Free radicals are highly reactive & bind double bonds extremely quickly & non-specifically
- These bonds can alter the structure of proteins, nucleic acids, and lipids
This can lead to:
- Disruption of the plasma membrane/ organelles (M)
- Abnormal folding of proteins (P)
- DNA mutation & breaks (D)
