1
Q
What are the four types of ultrastructural changes of reversible cell injury?
A
- Plasma membrane alterations
- mitochondrial changes
- dilation of the ER
- nuclear alterations.
2
Q
What are the structural changes seen in irreversible cell damage?
A
- Increased eosinophilic in H&E stains due to loss of cytoplasmic RNA 2. Glossy homogenous appearance due to loss of glycogen 3. large vacuolated cytoplasm = myelin figures 4. Nuclear changes: karyorrhexis, karyolysis, pyknosis
3
Q
What are the three mechanisms by which calcium can cause cellular damage?
A
- The accumulation of Ca in mitochondria results in opening of the mitochondrial permeability transition pore and failure of ATP generation. 2. Increased cytosolic Ca2+ activates a number of enzymes with potentially deleterious effects on cells. These enzymes include phospholipases (which cause membrane damage), proteases (which break down both membrane and cytoskeletal proteins), endonucleases (which are responsible for DNA and chromatin fragmentation), and ATPases (thereby hastening ATP depletion). 3. Increased intracellular Ca2+ levels also result in the induction of apoptosis, by direct activation of caspases and by increasing mitochondrial permeability.
4
Q
What is the definition of an infarct?
A
A localized area of coagulative necrosis.
5
Q
What type of necrosis is usually paired with gangrene necrosis?
A
Coagulative necrosis
6
Q
What is the difference between wet and dry gangrene?
A
Wet gangrene includes a bacterial infection that occurs with more liquefactive necrosis.
7
Q
Describe the major characteristics of coagulative necrosis. Also include histologic changes.
A
Coagulative necrosis: - tissue maintains structure; firm - eosinophilic and enucleate - no proteolysis because the injury has destroyed enzymes and proteins - cells removed by phagocytosis EX: ischemia due to blood vessel obstruction
8
Q
Describe the major characteristics of liquefactive necrosis:
A
- ENZYMATIC DIGESTION of dead cells - due to bacterial or fungal infections where enzymes are released from leukocytes - necrotic material is called pus EX: bacterial infection (abscess formation), brain infarcts
9
Q
Describe the major characteristics of caseous necrosis:
A
- cheese like appearance - microscopically looks like a collection of necrotic cells and debris surrounded by activated macrophages - has relation to granulomatous inflammation EX: tuberculosis infection
10
Q
Describe the major characteristics of fibrinoid necrosis:
A
- Injury to blood vessels - deposition of immune complexes in blood vessel - fibrinoid is formed from combination of immune complexes and fibrin EX: immune reactions
11
Q
Describe the major characteristics of fat necrosis:
A
- no specific pattern of necrosis - forms calcium soaps (fat saponification) - appears white and chalky EX: acute pancreatitis from release of lipases
12
Q
What is dystrophic calcification?
A
If necrotic cells and cellular debris are not promptly destroyed and reab- sorbed, they provide a nidus for the deposition of calcium salts and other minerals and thus tend to become calcified. This phenomenon, called dystrophic calcification.
13
Q
Describe the pathology of cystic fibrosis:
A
- mutation in CTFR (Cystic fibrosis transmembrane conductance regulator) gene (misfolded protein); defect in CTFR, a Cl- transporter - May cause emphysema: * defect in a1-antitrypsin gene = poorly folded AAT proteins = accumulation of AAT in ER of the lungs = emphysema - Impaired dissociation of the CTFR protein from chaperones causes many cases of cystic fibrosis. Emphysema (a component of COPD) is a lung condition that causes shortness of breath. In people with emphysema, the air sacs in the lungs (alveoli) are damaged. Over time, the inner walls of the air sacs weaken and rupture — creating larger air spaces instead of many small ones. This reduces the surface area of the lungs and, in turn, the amount of oxygen that reaches your bloodstream. Most people with emphysema also have chronic bronchitis. Chronic bronchitis is inflammation of the tubes that carry air to your lungs (bronchial tubes), which leads to a persistent cough.
14
Q
Describe the pathology of Familial hypercholesterolemia:
A
- mutation in LDL receptor (misfolded protein) = hypercholesterolemia
15
Q
Describe the pathology of Tay-Sachs:
A
- mutation of hexosaminidase b subunit (protein misfolding) = accumulation of GM2 gangliosides in the lysosomes of neurons
16
Q
Describe the pathogenesis of alpha-1-antitrypsin deficiency:
A
(misfolded protein) Storage of nonfunctional protein in hepatocytes causes apoptosis; absence of enzymatic activity in lungs causes destruction of elastic tissue giving rise to emphysema.
17
Q
Describe the pathogenesis of Creutzfeldt-Jacob disease
A
Abnormal folding of prions causes neuronal cell death
18
Q
Describe the pathogenesis of Alzheimers:
A
Abnormal folding of Ab peptides causes aggregation within neurons and apoptosis
19
Q
What is the fundamental cause of necrotic cell death?
A
Decrease in ATP
20
Q
What is the difference in ATP generation between the anaerobic and aerobic pathways?
A
Aerobic- 30 ATP Anaerobic- 2 ATP
21
Q
A reduction in ATP of what percentage is required for damage from a lack of ATP to occur?
A
5-10%
22
Q
Due to a lack of ATP, decreased activity of the Na/K pump will result in…
A
Cell swelling, ER dilation (> ribosome dissociation and decrease in protein synthesis)
23
Q
Due to a lack of ATP, decreased activity of the Ca2+ pump will result in…
A
influx of calcium causing damaging effects through the activation of enzymes
24
Q
Activation of enzymes and the opening of mitochondrial permeability transition pores is due to what factor?
A
A lack of ATP which disrupts Ca2+ channels, causing an influx of cytoplasmic calcium (first from intracellular stores, then from extracellular compartment)
25
What ion(s) flow through the mitochondrial permeability transition pores?
Hydrogen ions, which will decrease ATP
26
How does formation of a mitochondrial permeability transition pore lead to the development of cell necrosis?
The PTP allows for the release of hydrogen ions from the mitochondria. H+ is required by ATP synthase to convert ADP to ATP. Thus, a loss of H+ = a loss of ATP = cell necrosis
27
How can ROS be produced from the mitochondria?
The mitochondria normally produces, but degrades ROS during respiration. With damage of the mitochondria, ROS are not able to be degraded.
28
To minimize the formation of ROS, a total of 4 electrons are transferred to oxygen to form water. What products are formed by the transfer of 1, 2, and 3 electrons to oxygen?
1. superoxide anion (O2-) 2. hydrogen peroxide (H2O2) 3. Hydroxyl ion (OH-) 4. Water
29
What enzyme is responsible for the conversion of superoxide anion to hydrogen peroxide?
SOD (superoxide dismutase)
30
What enzyme(s) are responsible for the conversion of hydrogen peroxide to water?
Glutathione peroxidase, catalase
31
What are the pathological effects of excess ROS like hydroxyl radicals?
1. Lipid peroxidation = membrane damage 2. Protein modifications = breakdown, misfolding 3. DNA damage = mutations
32
List antioxidants responsible for the removal of ROS:
- Vitamin E - Vitamin A - ascorbic acid - glutathione
33
List the enzymes (and their locations) responsible for the removal of ROS:
- catalase (from peroxisomes) - SOD (mitochondria) - Glutathione peroxidase (mitochondria)
34
T or F: membrane damage is a consistent feature of most forms of cell injury including apoptosis?
False
35
Describe four effects of repercussion injury:
1. Overload of Ca2+ \> phospholipase activation = membrane damage = PTP = low/no ATP 2. Formation of ROS 3. Inflammation due to recruitment of neutrophils 4. Complement activation due to deposition of IgM antibodies. restored flow causes complement proteins to bind to antibodies and become activated.
36
What cyclin and CDK combinations are responsible for regulation of G1 to S phase and G2 to M phase?
G1 - S: Cyclin D- CDK 4, CDK 6 G2-M: Cyclin B- CDK 1
37
What are three main CDK inhibitors for the regulation of the cell cycle from G1 to S phase and G2 to M phase?
1. p21 2. p27 3. p57
38
What are the two main morphological features of apoptosis? What is the most characteristic feature of apoptosis?
1. Cell shrinkage (dense, deeply eosinophilic cytoplasm) 2. Chromatin condensation (most characteristic feature) Chromatin condensation is the most characteristic
39
What four physiological steps are largely involved in apoptosis?
1. Cell shrinkage/DNA fragmentation 2. Membrane blebbing 3. Apoptotic bodies 4. Phagocytosis of apoptotic bodies
40
What are the two phases of apoptosis, and what occurs in each phase?
1. Initiation phase (mitochondrial or death receptor pathway): activation of caspases 2. Execution phase: caspases trigger degradation of critical cellular components
41
Which of the two apoptotic pathways in the initiation phase eliminates self-reactive lymphocytes, and which one is for most physiological and pathological situations?
self-reactive lymphocytes: Death receptor pathway (Extrinsic) Other: Mitochondrial pathway (Intrinsic)
42
BCL2, BCLX, and MCL1 are principal members of what family involved in the intrinsic pathway for apoptosis?
Members of the anti-apoptotic family; Cellular injury, DNA damage, or decreased hormonal stimulation leads to inactivation of BCL2. Lack of BCL2 allows cytochrome c to leak from the inner mitochondrial matrix in the cytoplasm and activate caspases. (clue: remember that factors with "CL" are anti-apoptotic)
43
BAX and BAK are members of what family involved in the intrinsic pathway for apoptosis?
Pro-Apoptotic- promotes mitochondrial outer membrane permeability
44
BAD, BIM, BID, Puma and NOXA are members of what family involved in the intrinsic pathway for apoptosis?
Regulators: their up regulation will result in the initiation of apoptosis
45
Detail the the steps of the intrinsic pathway for apoptosis:
- in the cytoplasm, cytochrome c nimbus to apoptosis activating factor 1 - this complex then binds to caspase 9 (the critical initiator of the intrinsic pathway) - the caspase 9 cleaves and activates adjacent caspase 9 molecules - activation of proteins that mediate the execution phase of apoptosis
46
Detail the steps of the extrinsic pathway for apoptosis:
- activation of death receptors by FasL (ligand found on lymphocytes) - once bound to Fas (receptor on cell), trimerisation of the death domain occurs -Binding of FADD - activation of caspase 8! - activation of executioner caspases
47
p53 is responsible for arresting the cell cycle at what phase?
at the G1 phase by activating p21
48
At the light microscopic level, what causes cellular swelling?
Failure of energy dependent membrane ion pumps.
49
At the light microscopic level, what causes fatty change?
impaired fatty acid oxidation due to ER dysfunction
50
What is meant by hydropic change?
Cellular swelling
51
T or F: You can expect to see steatosis and cellular swelling with reversible cell injury? What are the causes of each characteristic?
True. Cellular swelling is due to malfunction of the ion pumps. Steatosis is due to failure of fatty acid oxidation.
52
T or F: You can expect to see mitochondrial swelling, loss of microvilli and membrane blebbing as ultrastructural features of reversible cell injury?
True
53
What are the two phenomenon that characterize irreversibility of cell damage?
1. Severe mitochondrial damage 2. Severe loss of membrane integrity
54
What is "ER" stress?
When the demand for protein folding is much greater than the capacity for protein folding. Recall, accumulation of unfolded protein can be due to: - metabolic alterations that decrease energy stores - genetic mutations in proteins, chaperones - viral infections - chemical insults
55
If a cell cannot adapt to misfiled proteins, apoptosis occurs. What is a method by which adaption of a cell to misfiled proteins can occur?
The cell can decrease the synthesis of the protein and increase synthesis of chaperone proteins.
56
Why does ischemia cause more rapid and severe tissue injury than hypoxia alone?
Because ischemia involves a decrease in oxygen due to reduced blood flow and affects both aerobic and anaerobic glycolysis. Hypoxia only affects aerobic glycolysis, not affecting anaerobic.
57
What is the main factor causing the opening of mitochondrial permeability transition pores?
increased calcium concentrations.
58
A characteristic of reversible cell injury is vacuolated cytoplasm. What is the mechanism behind this occurrence?
Vacuolation is the result of dispersion of organelles and dilution of cytosolic proteins by the influx of water.
59
A decrease in pH, due to an increase of lactic acid via an increase in anaerobic glycolysis, will result in what structural feature?
Clumping of nuclear chromatin. Chromatin condensation and cell swelling are the two early identifiers of an injured cell.
60
What are the four mechanisms by which tissue-reperfusion can cause further injury?
1. Complement activation (IgM activates compliment system) 2. Inflammation (neutrophils to area are increased blood flow) 3. Increased Calcium influx 4. Formation of ROS
61
How can ROS cause cell membrane disintegration?
Free radicals, with their unpaired electron, are prone to extract a H+ from the polyunsaturated fatty acids in cell membranes. The fatty acid that loses a H+ becomes, itself, a free radical that can then be oxidized to an even more reactive radical that will extract a H+ from the neighboring fatty acid, propagating a chain reaction that leads to membrane disintegration.
62
What are the hallmark characteristics of reversible vs. irreversible cell damage, and cell death?
Reversible- cellular swelling Irreversible- membrane damage Cell death- loss of the nucleus- nuclear condensation (pyknosis), nuclear fragmentation (karyorrhexis), and dissolution (karyolysis)
63
What is 'red infarction'?
When blood reenters a loosely organized tissue.
64
Detail the extrinsic receptor-ligand pathway:
FAS ligand binds to FAS death receptors on the target cell, activating caspases. TNF minds TNF receptor on the target cell, activating caspases.
65
Cytotoxic T cells have an ability to kill virally infected cells. What is the mechanism of action?
Perforins secreted by CD8+ T cells creates pores in membrane of target cell. Granzyme from CD8+ T cells enters pores and activates caspases.
66
in Alzheimer's disease, aggregation of beta-amyloid plaques causes symptoms. What other disease is linked to Alzheimer's?
Down syndrome The gene for b-APP is on chromosome 21. Thus, most individuals with Down syndrome develop Alzheimer's disease by the age of 40 (early-onset)
67
T or F: phosphorylation and dephosphorylation of key proteins regulate DNA replication, mitosis, and cytokinesis?
True
