Cell Injury and Death Flashcards
Cell response to injury is dependent on what four factors?
Dose
Duration
Type of injury
Type of cell
Cell injury results when what happens?
Cells are stressed so severely that they are no longer able to adapt
What types of cells are most affected by chemo?
Epithelial cells of the intestine, or any cells that replicate continuously
What are the three permanent cell types?
Skeletal muscles cells
Cardiac cells
Neurons
What are the two outcomes of irreversible injury to a cell?
Necrosis or apoptosis
What are the five main cellular components (processes/structures) that are damaged during cell injury?
- Aerobic respiration
- Integrity of cell membranes
- Protein synthesis
- Cytoskeleton
- Genetic apparatus
What are the three components of cell that undergo damage?
Membranes
Proteins
DNA
(MPD)
What are the five major biochemical mechanisms of cell injury?
- Ca influx into cell
- ROS accumulation
- ATP Depletio
- Mito damage
- Permeability of membrane changes
(CRAMP)
Are all free radicals bad?
No–we need them
Excess Ca causes what? (2)
Activation of enzymes
Changes permeability of Mitochondria, restricting ATP production
What are the four major enzymes that Ca influx activates?
- Phospholipases
- Proteases
- Endonucleases
- ATPase
What are the three major sources of Ca excess?
- ER stores
- Malfunction of Na/Ca pumps
- Extracellular Ca
What is the main organelle that is affected by Ca influx?
Mito
How is damage to the mito by Ca influx effected?
Breakdown of phospholipids (A2 and sphingomyelin) via enzymes activated by Ca. These lipids can be damaging
What happens when the Mitochondrial membrane is damaged?
Loss of H+ gradient, therefore loss of ATP
A decrease in oxygen affects the mitochondria how? (4)
Decrease ATP generation
ROS go up and leak out
Increase in proapoptotic proteins
Decrease in anti-apoptotic proteins
What is the effect of CN?
Inhibits the ETC, (cyt C) inhibiting ATP production
What happens when oxidative phosphorylation cannot proceed and ATP levels decrease? (3)
Na is not able to be pumped out, causing water influx and efflux of K
Anaerobic glycolysis (lactic acid)
Detachment of ribosomes (decreased protein synthesis)
What happens to the DNA when pH decreases?
Chromatin clumping (DNA damage)
What happens to out membranes with age? What is the consequence of this?
Leaky membranes, leaking ROS
True or false: normal metabolism leads to ROS production?
True
Why are ROS bad?
Bind to whatever double bond that’s around
What happens when someone is put on 100% O2?
ROS production
Reperfusion injury is caused by what?
ROS production increases but enzymes to take care of it are not around
Why do PMNs produce ROS?
Part of immune response
What are the four major ROS?
O2-
OH -
ONOO -
Lipid peroxide radicals
Where do ROS affect lipid membranes? What is produced?
The double bonds of FAs
This leads to peroxide formation, and continues
What are the vitamins that are antioxidants (4)?
C, E, A and beta-carotene
What happens to proteins with ROS? (2)
Side chain oxidation leads to change in structure (enzymes die)
Form disulfide bonds
Free radical interaction with thymine leads to what? What can this lead to?
Single-stranded breaks in DNA
CA
What is the function of superoxide dismutase?
O2 to H2O2
What are the ROS enzymes that reduce free radicals? (3)
Superoxide dismutase
Glutathione peroxidase
Catalase
What are the steps of the respiratory burst of PMNs? (hint there are three enzymatic steps)
O2 converted to superoxide by NADPH oxidase.
SOD to H2O2 packed in granules for release
Myeloperoxidase also packs HOCl and Oh radical
What is chronic granulomatous disease?
The NADPH oxidase is malfunctioning
Pts die of infection early d/t granuloma infection
Damage to membrane permeability causes what three damaging process?
Release and activation of phospholipases
Decreased phospholipid re-acylation
Cytoskeleton damage via protease activation
What happens in reversible cell injury (4)?
Swelling of ER and mito,
Membrane blebs produced
Detachment of ribosomes from ER
Chromatin clumping
What happens in irreversible cell injury (6)?
- Lysosome rupturing
- Nuclear condensation
- Myelin figures produced
- Ribosome loss d/t swollen ER
- Holes in the membrane
- Swollen mito
What happens to renal tubules with reversible damage?
Raggedness, but nuclei are still intact
What happens to renal tubules with IRReversible damage?
Nucleus breaks and dissolved
Are renal tubule cells able to reproduce?
Yes
Is there a particular point when reversible to irreversible injury occurs?
no
What are the two forms of cell death?
Necrosis
Apoptosis
True or false: apoptosis and necrosis are always pathologic
False–apoptosis can be physiologic, but true for necrosis
What happens in necrosis that is so bad?
Leakage of cellular contents leading to inflammation
What is necrosis?
Uncontrolled cell death that does not require signals or activation of genes
What are the cytoplasmic changes with necrosis (3)?
Eosiniphilia
Glassy appearance
Vaculoation
What are the three nuclear changes with necrosis?
Pyknosis
Karyorrhexis
Karyolysis
Hypoxia can be the result of what factors?
- Loss of blood supply
- Decrease in oxygen carrying capacity of the blood
- Poisoning of the enzymes of the oxidative phosphorylation
Chemical injury to a cell leads to what?
to a disruption of the physical structure of the cell or to a breakdown of the biochemical processes of the cell
What is kwashiorkor?
inadequate protein intake
What is marasmus?
inadequate calorie intake
What are the six specific biochemical process seen in the process of cell necrosis? (what happens to ATP prodcution? Ca? ROS? Membrane permeability? Mitochondira? Cytoskeleton)?
- ATP depletion
- Loss of Ca
- Free radicals
- Defective membrane permeability
- mito damage
- Cytoskeletal damage
What is oxidative stress?
The accumulation of damage caused by oxygen-derived free radicals
What nucleic acid do free radicals react with to cause DNA damage?
Thymine
What is the function of Glutathione peroxidase?
Converts OH- to H2O2
What is the function of Superoxide dismutase?
Converts O2 radical to H2O2
What are the three areas of the cell that are affected by free radicals?
Membrane (lipids/FA)
Proteins
DNA
What are the changes seen in chronic cell injury?
Mito changes
Cytoskeletal changes
What is Pyknosis?
Nuclear material becomes condensed
What is Karyorrhexis?
Nuclear material breaks apart
What is Karolysis?
Nuclei have totally dissolved
How can aerobic respiration affected in cell injury?
Decreased ATP synthesis leads to lower Na/Ca pump activity, causing Ca influx
How can a compromise in integrity of the cell membrane lead to cell injury?
Increase in Ca influx or ROS leakage from cells
How can protein synthesis be affected in cell injury?
Either disulfide bonds are formed where there should be none, or there may be other changes in AAs
Also, ribosomes may fall off
What cause the chromatin clumping seen in cell injury?
Lowered pH, caused by increase in glycolysis
What happens to lysosomes during cell injury?
Can leak, causing severe damage to the cell
What happens to the ER in cell injury?
Swells, possibly leading to ribosome detachment
What happens to the mitochondria during cell injury? (4)
- Swelling
- loss of phospholipids reacylation/synthesis
- Decreased ATP
- Increased ROS
What happens to the cytoskeleton during cell injury?
Broken down d/t increase protease activity from Ca influx
What happen to the nucleus during cell injury?
fibrillar and granular components of the nucleolus may segregate
Can also undergo pyknosis
What are the three mechanisms of reducing ROS in a normal cell?
Superoxide dismutase
Glutathione peroxidase
Catalase
What is the reaction catalyzed by superoxide dismutase?
O2- to hydrogen peroxide
What is the reaction catalyzed by glutathione peroxidase?
OH radical to hydrogen peroxide
What is the reaction catalyzed by catalase?
Hydrogen peroxide to water and oxygen
When ROS react with lipids, what do they form? What is the consequence of this?
Peroxides, causes chain reaction
What are the four major changes that a loss of ATP leads to?
- Cellular organelle swelling
- Activated enzymes
- Chromatin clumping
- Decreased protein synthesis