Flashcards in Exam #1: Cell Injury & Death Deck (39):
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.
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?
What are the six mechanisms of cell injury?
1) ATP depletion
2) Loss of Ca++ homeostasis (i.e. Ca++ entry)
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?
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)
What are the six ways that oxygen radicals generated?
1) Excess O2 (breathing 100% oxygen can cause damage to the lung)
2) Inflammation (Neutrophils & macrophages)
3) Reperfusion injury
4) Chemical toxicity
5) Ionizing radiation
6) Chemical carcinogenesis
What are the four ROS?
Lipid peroxide radicals
Describe the process of lipid peroxidation of membranes.
- Double bonds of unsaturated fatty (at least one double bond) acids are attacked by ROS
- Peroxides are formed
- Peroxides are unstable and they react with membrane lipids to both damage them & form more peroxides
What vitamin in the membranes reduce ROS?
Vitamin E & A
What happens in the oxidation of proteins?
- Oxidation of side chains alters the structure & function of proteins
- Formation of disulfide bonds-->cross-linking
- Inactivation of enzymes
How do free radicals lead to DNA damage?
- Free radical interaction with thymine causes ssDNA breaks
- These mutations have been implicated in carcinogenesis
*****Long-term inflammation that is associated with increased production of ROS is linked to carcinogenesis
What enzymes in the cell are protective against ROS?
What reaction is carried out by SOD?
Converts oxygen radical into hydrogen peroxide
What reaction is carried out by Glutathione peroxidase?
Converts hydroxide radical into hydrogen peroxide
What reaction is carried out by Catalase?
Converts hydrogen peroxide into water & oxygen
What is the function of the neutrophil?
- Engluf & digest bactera
- Respiratory burst
Outline the process of respiratory burst.
1) NADPH oxidase reduces oxygen to the oxygen radical
2) Oxygen radical is acted upon by superoxide dismutase to make hydrogen peroxide
3) Myeloperoxidase converts hydrogen peroxide into Hypochlorus acid (HOCl) & Fentin reaction creates Hydroxide radical
What is the defect in Chronic Granulomatous Disease?
NADPH oxidase deficiency-->granulomas form from bacterial infection
*Patients die from overwhelming infection by 25
Outline the events that lead to an increase in membrane permeability.
1) ROS--> lipid peroxidation & phospholipid loss
2) Hypoxia-->Decrease ATP-->decreased phospholipid synthesis
3) Ca++ activation of phospholipase-->phospholipid breakdown
4) Protease activation by Ca++-->cytoskeletal damage
*Net result is membrane damage
What is reversible cell injury?
If damage is not too severe, cells can repair themselves so that the damage is reversible
- E.g. liver & kidney
What is irreversible injury?
Point of no return has passed. Cells cannot recover from the accumulated damage and they die
What are signs of cellular injury that are reversible?
- Swelling of cell and organelles
- Membrane blebs
- Chromatin clumping
*****You can recover from this and go back to homeostasis
What are signs of irreversible cellular injury?
- Swelling of ER & loss of ribosomes
- Lysosome rupture
- Swollen mitochondria with amorphous densities
- Nuclear condensation (pyknosis)
- Fragmentation of cell membrane & nucleus
What is pyknosis?
Irreversible condensation of chromatin in the nucleus of a cell undergoing necrosis or apoptosis
What is the point at which reversible injury becomes irreversible?
There is no exact point that marks this transition
What is the difference between necrosis & apoptosis?
Necrosis is always pathologic; apoptosis can be physiologic or pathologic
Necrosis= cell death that is not controlled by the cell and does not require the signals or activation of genes
What cytoplasmic changes are seen in necrosis?