Chapter 2 Robbins/Pathoma Flashcards
What is involved in cellular senescence? (2 things)
telomere shortening –> puts them in a non-dividing state
activation of tumor suppression genes
Myositis ossificans?
what do you see on Xray?
inflammation of the connective tissue (mesenchymal cells) in muscle results in a metaplastic production of bone in response to trauma.
Bone that is NOT connected to the original bone.
is pathological hyperplasia cancer?
exception?
no, but it can progress to cancer –> endometrial hyperplasia can become endometrial carcinoma
benign prostatic hyperplasia is NOT associated with cancer
Metaplasia is what?
1) what is the definition
2) what is the most common place to find metaplasia?
3) common pathology and what is the change going from? (what is the name to know)
stress on the organ changes, then the organ will respond by changing its tissue type
Lines body surfaces
Barrett Esophagus –> squamous to columnar (columnar metaplasia). –> stomach acid refluxing up
How does metaplasia occur?
key thing to note about metaplasia?
reprogramming of STEM cells
REVERSIBLE process. if you remove the stress, it will result in metaplasia
What are the two mechanisms by which chemicals induce cell injury?
what organ is chiefly affected?
Direct toxicity or Conversion to a toxic metabolite
liver –> it’s doing the conversion.
What is defects in membrane permeability consistent with? exception?
cell injury
except apoptosis
you see alkaline phosphatase and transaminase levels elevated in the blood, what does it indicate?
irreversible damage of the liver.
“dry cleaning industry”… what happened and what created this problem? what do you see?
what is another way this type of toxicity could be presented?
conversion of a toxic metabolite –> CCL4 to CCL3 free radical.. this was done by Cytochrome P450 –> because this is occurring in the liver and you’re destroying protein creation from the free radicals, you see less apolipoproteins so fat accumulation!
Acetominophen –> converted to a toxic product by the liver.. hence you die if you take too much
What are Russell bodies?
Plasma cells that are producing excessive amounts of Its results in the ER becoming distended, producing large, characteristically eosinophilic inclusions.. Russell bodies
5 common causes of injury?
Inflammation
Nutritional deficiency or excess
Hypoxia
Trauma
Genetic Mutations
why might decreasing vein flow cause ischemia?
2 examples?
block the vein –> block the flow of blood across the bed so decrease in amount of oxygen within the organ.
Bud Chiari Syndrome –> blocking hepatic vein going to the liver because of another possible thing (polycythemia vera)
hypercoaguable states
Explain Cellular swelling in injury
you cut the Na/K pump that needs ATP. so Na stays accumulating inside –> water comes in and swells
what are the three endogenous pigments to know?
what PATHOLOGIES ARE THEY ASSOCIATED WITH?
Lipofuscin granules –> “wear and tear”.. seen on old hearts and livers –> TELLTALE SIGN of free radical injury and lipid peroxidation
melanin –> only endogenous brown-black pigment
hemosiderin –> storage for iron.. present when there’s tons of iron and ferritin micelles come together and form hemosiderin. —> local excess is seen in tissue hemorrhage!!!! (bruise, or hemorrhaging after necrosis)
what three things are pathologic with regards to free radicals?
1) lipid peroxidation of membranes –> destroy membranes
2) modification of proteins
3) lesions in DNA (double strand or single strand breaks)
What is causing atherosclerosis?
smooth muscle cells and macrophages in arteries and the aorta fill up with lipid vacuoles –> made of cholesterol and cholesterol esters
Pyroptosis?
programmed cell death that is accompanied by the release of IL1.
What happens because of the swelling of the RER?
ribosomes pop off and so protein synthesis of
Hypoplasia:
1) what is it?
2) hallmark?
decrease in cell production during embryogenesis –> resulting in a small organ
streak ovary in turner syndrome
Aplasia?
failure of cell production during embryogenesis
when is hemosiderosis best seen?
common bruise
hemorrhaging after an infarct
What is used to removed free radicals?
1) antioxidants –> vitamin E or vitamin A
2) transport proteins of metals (transferrin, lactoferrin, ceruloplasmin) –> minimizes reactivity of metals
3) free radical scavenging systems
What is Hyaline Change?
alteration within cells or in the extracellular space that gives a homogenous, glassy, pin, appearance.
in long standing hypertension and diabetes mellitus, walls of arterioles (especially in the kidney) become hyalinized from so much deposition of basement membrane stuff.
What can Barrett Esophagus become if left untreated?
Adenocarcinoma
what is the morphologic hallmark of cell death?
what is the mechanism by necrosis?
what about apoptosis?
loss of nucleus
Pyknosis –> nucleus shrinks
Karyorrhexis –> breaks it into pieces
Karyolysis –> final stuff broken down
fragmentation into nucleosome-size fragments
what are the free radical scavenging systems (enzymes)
1) Catalase –> present in peroxisomes –> decompose H2O2 to O2 and H2O
Superoxide dismutase (SOD) –> converts O2- to H2O2
Glutathione peroxidase
Fat Necrosis
1) what is it
2) main appearance? what is this called?
3) what 2 places is this associated with?
necrosis of adipose tissue
chalky white appearance –> saponification
- -woman in car accident –> destruction of fat cells in the breast.
- peripancreatic fat
common types of physiologic hyperplasia?
female breast glandular epithelium hypertrophy during pregnancy
liver transplant people –> grows back to original side.
What are three examples of pathologic hyperplasia?
endometrial hyperplasia (estrogen)
Benign Prostatic Hyperplasia (androgens)
Papillomaviruses/other viruses
Niemann Pick Disease, type C?
lysosomal storage disease –> problem with cholesterol trafficking so cholesterol accumulation.
30 y/o woman presents fibrinoid necrosis, what could it be?
preeclampsia –> 3rd trimester women have elevated BP and they have fibrinoid necrosis of the placenta
What is the most common genetic abnormality found in human cancers?
TP53
What are the major triggers for physiologic hypertrophy?
pathologic?
mechanical sensors + mechanical stretch
growth factors and agonists or hormones
Werner Syndrome?
defective gene product in DNA helicase
What is the term for large, whorled phospholipid masses that are derived from damaged cell membranes?
what is their fate?
myelin figures
phagocytose or degraded to fatty acids –> saponification
Physiologic examples of apoptosis (2)
endometrial shedding
removal of cells during embryogenesis
elimination of potentially harmful self-reactive lymphocytes
say there’s ischemia in the brain or spinal cord, what is the most useful thing that is done in response?
inducing hypothermia –> lower metabolic demands and suppresses the formation of free radicals.
what three things can happen that lead to cellular aging?
what 3 ways can this happen?
1) telomeres are too short –> cell loss
2) DNA damage –> mutations
2) damaging of proteins –> decreased cell function
Main consequence of hypoxia?
what’s the immediate result because of this?
What 2 things cannot work because of this?
what is unregulated?
Impairs oxidative phosphorylation –> so no ATP being generated
1) Na-K pump, so you see high K+ outside, high Na+ inside (3 out, 2 in)
2) Ca2+ pump –> can’t hide ca2+ anywhere in the cell, so it’s going to activate a bunch of stuff
3) aerobic glycolysis –> creates a little bit of ATP but tons of lactic acid, so lowers the pH and destroys DNA and protein.
2 mechanisms of atrophy?
Apoptosis –> decrease # of cells
Ubiquitin-proteosome degradation pathway and Autophagy –> decreasing cell size
What quality shows that the cell injury is now irreversible?
Membrane damage
what 6 things help lead to atrophy?
1) someone in a cast
2) diabetics
3) atherosclerosis in old people (what is it called?)
4) impoverished countries
5) 55y/o female with a pituitary tumor
6) large benign tumor
1) muscle atrophy
2) loss of innervation
3) decreased blood supply (ischemia) leads to atrophy –> senile atrophy
4) nutritional problems
5) loss of endocrine stimulation –> no estrogen means atrophy of breast, endometrium, vaginal epithelium
6) pressure cam atrophy on surrounding tissues
Necrosis:
1) cells
2) what is it followed by?
3) generally, is it physiologic or pathologic
large groups of cells
acute inflammation
always pathologic
Keratomalacia is what?
metaplasia of the eye due to a vitamin A deficiency
Fibrinoid Necrosis
1) what is it?
2) what does it cause?
3) what are the two characteristics of it?
damage to the blood vessel wall
leaking of proteins of the blood vessel into the wall –> bright pink staining
Malignant hypertension + Vasculitis
What are the 4 types of adaptation cells do under stress to maintain a steady state of homeostasis?
Hypertrophy
Hyperplasia
Atrophy
Metaplasia
What happens with protein in most renal diseases? what findings are there and what do you see histologically?
is it reversible?
proteinuria –> excessive protein loss in the urine due to heavy glomerular filtration
because you’re trying to keep as much as possible, your proximal tubule reabsorbs a ton more and you’ll see the protein as pink hyaline droplets within the cytoplasm
yes, proteinuria gone, these vesicles diminish
What are the 3 major consequences of Mitochondrial damage?
1) creation of the Mitochondrial permeability transition pore
2) abnormal oxidative phosphorylation –> creates ROS
3) release cytochrome C to activate caspases
I’m a virus and I want to get around the extrinsic pathway of apoptosis. what do I produce?
FLIP –> protein that binds to pro-caspase 8 but doesn’t allow it to be cleaved –> no start to the extrinsic apoptosis pathway
What metaplasia goes from columnar to squamous? what also can lead to squamous metaplasia?
smokers, in which chronic irritation.
Vitamin A deficiency
Classic findings of CO poisoning?
Cherry red appearance of skin –> hemoglobin tightly bound that it reflects red light looking like they’re red, but actually hypoxic
headache
What are examples of Direct Toxicity?
Mercuric Chloride Poisoning
Cyanide Poisoning
what are the three membranes that are responsible for “membrane damage” that results in irreversible injury?
what pathology can be explained by each (if applicable)? otherwise what’s going to happen?
Plasma membrane damage –> leaking of cardiac enzymes.. you can tell that there was irreversible damage
Mitochondrial membrane –> leakage of cytochrome C causes apoptosis
Lysosomal membrane –> leaks lytic enzymes, destroying the membrane.
Caseous Necrosis
1) Characteristic appearance (2 names)
2) what 2 pathologies are associated with this?
3) characteristic to see on slide?
1) cottage cheese like, friable
2) fungal infection and mycobacterium TB
3) granulomatous inflammation
In duration of injury, what what are the effects of things happening in order?
Cell function goes down
Biochemical alterations (lead to cell death)
ultrastructural changes (not so important)
light microscopic changes
gross morphologic changes last
what is the major pathway of apoptosis in mammalian cells and how does it work?
1) what primary group is involved?
intrinsic pathway (hallmark is BCL2 family)
BH3 only cells “sense” that there is damage –> activate BAX and BAK, and inhibit BCL2/BCL-XL which are antiapoptotic stuff –> release cytochrome C
cytochrome C binds to APAF1 –> creates apoptosome –> binds to caspase 9 –> cleavage and activation of execution phase
this is the activation of Caspase 3 and 6 –> activate DNAse activity and destroy the insides
Explain what happens whet happens when we have the mitochondrial permeability transition pore open?
leads to loss of mitochondrial membrane potential, so bad oxidative phosphorylation.
Protein Cyclophilin D –> targeted by cyclosporine which is used to close this channel (used to prevent graft rejection)
say a mammalian cell is first dealing with hypoxic stress. what transcription factor is unregulated and what does it do?
hypoxia inducible factor 1
creates new blood vessels, stimulates cell survival pathways, and enhances anaerobic glycolysis.
Hyperplasia
1) what is the definition?
2) mechanism?
3) what constitutes physiologic hyperplasia?
4) what constitutes pathologic hyperplasia?
increase in number of cells in an organ or tissue in response to a stimulus.
result of growth factor driven proliferation off mature cells and from tissue stem cells!
due to the action of hormones or growth factors (there’s a need to compensate for increase functional activity)
due to an inappropriate action of hormone or growth factors acting on target cells
The uterus undergoes what type of growth? explain
Hyperplasia and hypertrophy
uterus increases in size when pregnant to accommodate for the space of the uterus
smooth muscle undergoes hyperplasia as well.
What causes emphysema?
a1-antitrypsin deficiency –> mutations slow protein folding, so you have a buildup of partially folded intermediates in the ER and liver.
3 causes of hypoxia?
Ischemia
Hypoxemia
Decreased O2 Carrying capacity of the blood
what two phenomena consistently characterize irreversibility?
inability to reverse mitochondrial dysfunction
disturbances in membrane function.
What’s different between apoptosis and Necroptosis?
what’s the general process of it?
necroptosis doesn’t result in the caspase pathway
TNFR1 is ligated –> recruits RIP1 and RIP3 –> generates ROS and damages mitochondria, reducing ATP
Liquefactive Necrosis
1) why is it called that?
2) where does it occur (2 places)
3) what structure can be seen with this?
1) enzymatic lysis of cells that leaves it liquidy
2) brain due to microglia, and inner pancreas from pancreatitis
3) abscess
Atrophy is what?
1) why is it?
2) what decreases?
results from decreased protein synthesis and increased protein degradation due to reduced metabolic activity
decreases both size of cell and number of cells
Cyanide is an example of what?
damage to the mitochondria, resulting in low ATP and eventually cell injury
Dystrophic vs Metastatic calcification?
where is dystrophic almost always found?
where are you going to find metastatic calcification?
dead or dying tissue, but calcium deposits on the tissue because it’s dying
metastatic means serum calcium or serum phosphate is elevated so it can deposit at all tissues of the body.
advanced atherosclerosis
people with hyperparathyroidism, bone tumors having higher bone resorption, vitamin D related stuff, renal failure
What is the predominating biochemical pathway involving muscular hypertrophy?
what does it signal?
PI3K/aKT pathway
Gata4, NFAT, MEF2 –> work to increase synthesis of muscle prteins.
what does TP53 do? what happens if its mutated?
it’s triggering p53 apoptosis when it sees that cells that are DNA damaged
cells with damaged DNA aren’t able to p53-mediated apoptosis –> and survive.
what two things are helping with anti-aging?
specifically, what does caloric restriction do?
what are both doing to counteract aging?
chaperone proteins (without them, in mice they aged super fast)
caloric restriction –> reduces the IGF-1 pathway but increases sirtuins (increase longevity I guess)
both are helping increase DNA repair and increase protein homeostasis
You want to remove the apoptotic bodies. what are two things that can coat these guys to help macrophages come and eat them?
thrombospondin
C1q from the complement system
Dysplasia is considered what?
what are the classic examples of dysplasia
proliferation of precancerous cells
Barretts –> adenocarcinoma
endometrial hyperplasia –> endometrial carcinoma
Hypertrophy:
1) what increases
2) what are the 2 mechanisms
3) what 3 tissues undergo hypertrophy only
Cell size
in order to accommodate a bigger cell, we need to increase the cytoskeleton –> so increased protein synthesis..
also we need to produce more organelles for larger cellular function
Cardiac myocytes, skeletal muscle, nerves
What are the anti-apoptotic members of the BCL family?
what is their function?
what is the major “sensor” of the BCL family?
BCL2, BCL-XL, and MCL1
prevent leakage of cytochrome C and other death-inducing proteins into the cytosol
BCL3
During autophagy, the autophagosomal membrane elongates, surrounds the cargo it wants to eat, and closes around it. what mediates this process and is also a good marker for identifying cells with autophagy?
what is autophagy prominent in?
LC3 (microtubule associated light chain 3)
atrophying cells
Mammogram looks at what? why is this important?
can indicate ductal carcinoma in situ –> fat necrosis would show calcification in the mammogram
what two diseases are associated with increased rates of autophagy?
huntingtons and alzheimers
Failure to produce one kidney is an example of what “plasia”?
aplasia
Autophagy?
cell consumes its own components in vacuoles
these vacuoles fuse with lysosomes to destroy it.
What two features of reversible cell injury can be seen under the light microscope?
again, when are we going to see this in the duration of
cellular swelling and fatty change
2nd to last
Where do we get free radicals from? (6)
1) normal redox reactions
2) ionizing radiation –> can hydrolyze water to OH and H free radicals –> Super dangerous
3) leukocytes during inflammation
4) chemicals and drug metabolism –> CCL4
5) Transition metals –> free iron and copper help form this.. think Fenton reaction
6) NO –> chemical mediator that can be converted to ONOO- or NO2 and NO3
What can decrease Oxygen carrying capacity of the blood?
3 major pathologies
Anemia –> decreases the total amount of RBC so decreasing the amount of oxygen going to the tissue
CO poisoning –> CO binds Hb 100x more than O2 so binding sites are taken up.
Methemoglobinemia –> Fe2+ usually binds O2, but it’s oxidized to Fe3+ from sulfa or nitrate drugs –> can no longer bind iron
Pathogenesis is what?
Etiology?
Morphology?
sequence of cellular, biochemical, and molecular events that follow the exposure of cells or tissues to an injurious agent.
Causes
structureal alteraltions
What enzymes do Ca2+ activate when it’s at high levels in the failing cell?
Phospholipase
proteases
endonucleases
ATPases
Most common exogenous pigments?
what do they present with?
what is an exogenous pigment found on the skin?
Carbon –> pollution, coal miner, smoking
anthracosis –> blackened tissues of the lungs
tattoos
Hallmarks of initial phase of injury? 5 things
what’s important to know about these hallmarks?
Cellular swelling Loss of microvilli Membrane blebbing Swelling of RER clumping of chromatin
show reversible stuff!
Ubiquitin-proteosome degradation pathway?
If you have a cell that needs to shrink, you need to destroy the cytoskeleton –>
ubiquitin is tagged on the intermediate filaments of the cytoskeleton
proteasome organelle in THAT cell recognizes the ubiquitin tagged proteins and destroys the proteins in the cell.
3 ways that ischemia happens? (examples of each)
Block in the arterial flow into the organ –> atherosclerosis
Decrease in flow through the vein
Shock –> septic, anaphylactic, neurogenic, etc.
What is the Extrinsic Pathway of Apoptosis
1) FAS ligand (on T cells) finds FAS death receptor (CD95) on the target cell (or another death receptor is TNFR1)
2) activates the Fas associated death domain (FADD)
3) binds and cleaves caspase 8
4) lead to execution tase (activating caspase 3 and 6)
Coagulative Necrosis?
1) texture
2) on a slide what do you see
3) what shape
4) where does it occur
5) what is the term for a localized area of coagulative necrosis?
6) what is coagulative necrosis called when it’s on the extremities? who is it associated with? what is to know about its characterization?
Firm and retain shape (coagulate)
no nucleus, but architecture still there.
3) wedge-shape
4) everywhere except the brain
5) infarct
6) Gangrenous –> it’s a clinical term, NOT A PATTERN. diabetics. dry without infection on top, wet with infection
What can create hypoxemia?
3 pathologies
Hypoventilation (more CO2 than O2)
COPD –> air trapped in lungs
interstitial fibrosis
What is the problem with reperfusion to ischemic tissues? (2 major consequences)
what if you reperfuse an ischemic heart?
deoxygenation to tissues –> have more blood go with more oxygen –> the tissues really aren’t able to use the oxygen correctly and instead make free radicals –> hurt the tissue more
more Ca2+ comes, favoring the opening of the mitochondrial permeability transition pore –> more ATP loss.
you’ll have even higher troponin and other cardiac. enzymes in blood work –> made it worse
Findings of Methemoglobinemia?
treatment?
chocolate colored blood
newborns do not have enzymes to reduce iron to 2+ state.
IV methylene blue changes Fe3+ to 2+
most common cause of signifiant fatty change in the liver?
alcoholic abuse, nonalcoholic fatty liver disease (from diabetes and obesity)
