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How does mitochondrial damage occur?
High conductance channels form in inner mitochondrial membrane which dissipates proton gradient. Cytochrome C also leaks out into cytosol and activates apoptosis.
What is the function of cytochrome C?
activates apoptosis
What is the "mitochondrial permeability transition"?
Pathologic high conductance channels formed on inner mitochondrial membrane.
What are the 4 actions caused by increased cytosolic Ca++?
1) Decreased ATP via ATPases
2) Decreased phospholipids via phospholipase
3) Disruption of membrane and cytoskeletal proteins via proteases
4) Nuclear chromatin damage via endonucleases
What 3 factors cause mitochondrial permeability transition?
1) increased cytosolic Ca++
2) oxidative stress
3) lipid peroxidation
True/False: Ischemia injures tissues slower than hypoxia?
False, ischemia injures tissues faster.
What is the first effect that hypoxia has on a cell?
Reduced ATP generation due to reduced oxidative phosphorylation.
What are the major effects of decreased ATP synthesis by cells?
1) Cellular swellin/blebs/loss of microvilli/ER swelling due to decreased Na/K pump activity
2) chromatin clumping due to decreased pH due to increased glycolysis
3) lipid deposition due to decreased protein synthesis due to detachment of ribosomes from ER.
What causes ribosomes to detach from Rough ER?
1) decreasing pH
2) decreasing ATP
What are the 3 major mechanisms that can cause ischemia/reperfusion injury?
1) calcium bathing of compromised cells
2) reperfusion resuts in increased local inflammation
3) damaged mitochondria are unable to completely reduce oxygen which leads to free-radical production (antioxidant mechanisms are also compromised)
What are free radicals?
chemical species with a single unpaired electron in an outer orbital
How are free radicals generated?
1) redox reactions
2) from NO
3) absorption of radiant energy
4) metabolism of exogenous chemicals
What are the 3 ways that free radicals cause cell injury?
1) lipid peroxidation of membranes
2) DNA fragmentation
3) cross-linking of proteins
How do free radicals damage lipid membranes?
Double bonds in membrane polyunsaturated lipids are vulnerable to attack by oxygen-derived radicals.
What is a harmful byproduct of lipid-radical interactions?
How do free radicals cause DNA fragmentation?
By reacting with thymine in nuclear and mitochondrial DNA to produce single-strand breaks.
How do free radicals cause the cross-linking of proteins?
By promoting sulfhydryl-mediated protein cross-linking.
What are the 4 ways that cells inactivate free radicals?
1) superoxide dismutase
2) Glutathione
3) Catalase
4) endogenous antioxidants
What reaction does superoxide dismutase catalyze?
forms hydrogen peroxide from superoxide (O2-)
What reaction does glutathione peroxidase catalyze?
breakdown of hydroxide radical to water
What reaction does catalase catalyze?
The degeneration of hydrogen peroxide into water and oxygen
Where is catalase found?
What are the 2 general mechanisms that allow chemicals to damage cells?
1) Directly combining with molecular components/organelles
2) By being converted to toxic metabolites that can act on target cells.
How does mercuric chloride poisining work?
Acts on membrane sulfhydryl groups to
1) Inhibit membrane ATPase dependent transport
2) Increase membrane permeability
How does carbon tetrachloride damage cells?
via autocatalytic membrane phospholipid peroxidation which leads to swelling and dissociation of ribosomes from SER and RER leading to reduced lipoprotien export due to inability to synthesize apoprotein.
What molecule is most reponsible for converting chemicals to toxic substances?
P-450 oxidase
In what organelle is the P-450 oxidase found?
In the smooth endoplasmic reticulum
In what organ is CCL4 prinicapally metabolized?
In the liver
How does CCL4 poisining lead to fatty liver?
Due to decreased synthesis of apoprotein leading to reduced exportation of lipoproteins and buildup of triglycerides in the cell
What is the difference between a lysosome and a peroxisome?
-Lysosomes get rid of macromolecules that have been phagocytosed as well as senescent organelles
-peroxisomes get rid of toxic substances such hydrogen peroxide
What are the 2 ways that mammalian cells can degrade cellular material to undergo atrophy?
1) lysosomes
2) ubiquitin-proteosome pathway
What is a morphological hallmark of cells undergoing atrophy?
Increases in the number of autophagic vacuoles.
What are the 2 ways that cells can undergo atrophy?
1) decrease in cell size
2) decrease in cell #
What are 2 stimuli for cardiac hypertrophy?
1) mechanical triggers (increased muscle stretch)
2) trophic triggers (increased α-adrenergic receptor activation)
True/False, cells undergoing hypertrophy have higher DNA content than normal cells?
What are the 2 types of hyperplasia?
1) physiologic
2) pathologic
What are the 2 types of physiologica hyperplasia?
1) hormonal hyperplasia
2) compensatory hyperplasia
What is an example of hormonal hyperplasia?
The proliferation of glandular epithelium of the female breast at pubert and during pregnancy
What is an example of compensatory hyperplasia?
Occurs when a portion of a tissue is removed or diseased, as in partial liver resection
What is the cause of most forms of pathologic hyperplasia?
excessive hormonal or growth factor stimulation
What is the difference between hyperplasia and cancer cells?
Cancer cells continue to proliferate without growth factors whereas hyperplastic cells stop growing after growth factors have stopped. Additionally, cancer cells have DNA damage whereas hyperplastic cells do not.
True/False: Metaplasia is irreversible?
False, metaplasia is reversible
True/False: Metaplasia arises by "genetic reprogramming" of epithelial stem cells or undifferentiated mesenchymal cells in connective tissue?
What types of metaplasia are common in trachea and bronchi?
Normal ciliated columnar epithelial cells are replaced by stratified squamous epithelium which is more "rugged".
During chronic gastric reflux, what type of metaplasia occurs?
stratified squamous becomes columnar epithelium (different than in bronchi and trachea)
What are primary lysosomes?
Membrane bound intracellular organelles containing a variety of hydrolytic enzymes that fuse with vacuoles containing material that needs to be ingested.
What are the 2 types of processes that lysosomes are in involved in?
1) heterophagy
2) autophagy
What are lipfuscin pigments?
Granules that represent indigestible material from intracellular lipid peroxidation.
What is "induction" of SER?
Hypertrophy of SER
What is the purpose of enzymatic modifications in the P-450 mixed function oxidase system?
increase the solubility of compounds to facilitate their excretion.
What is the relationship between alcohol and barbituates?
The use of alcohol causes hypertrophy of SER which allows the cell to more efficiently excrete barbituates thereby reducing the therapeutic levels of the barbituate.
True/False: The # of mitochondria increase in a cell during hypertrophy?
What are phagosomes
phagocytic vacuoles
What are autophagic vacuoles?
Vacuoles that contain intracellular proteins/organelles that are to be digested.
What is Kartegener syndrome?
Immotile cilia syndrome, found in respiratory epithelium. Causes chronic bacterial infections due to malfunctioning microtubules in cilia
What is the effect of colchine?
It is a drug that prevents microtubule polymerization thereby preventing the movement of macrophages. It is used to treat gout.
What are the functions of vina alkaloids?
They bind the microtubules involved in mitotic spindles thereby anatgonizing cellular proliferation. They are used to prevent tumor growth.
What are the 3 functions Heat Shock Protiens?
1) maintain proper protein folding
2) preventing pathologic protein aggregation
3) transporting prtoeints into intracellular organelles.
What is another name for heat shock proteins?
What happens when HSP's cannot fix irregularly folded proteins?
The irregularly folded proteins are tagged and bound to ubiquitin for catabolism in proteosomes.
What are examples under which synthesis of HSP's is increased?
1) After myocardial infarction
2) after neuronal ischemic injury.
When are HSP's most ubiquitously expressed?
When cells are undergoing sublethal stresses.
What are the 3 general ways that cells can accrue intracellular accumulations?
1) increased production of an endogenous substance
2) defects in metabolism, packaging, transport, or secretion of endogenous substances
3) abnormal accumulation of exogenous material.

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