Path Ch1/2 Cellular Responses to Stress and Toxic Insults: Adaptation, Injury, and Death

you see active caspases in a cell. what does this mean?

active apoptosis

Hypertrophy can cause a "switching" of cells/genetic expression What does this mean and whats an example?

adult -> fetal form muscle hypertrophy: alpha mysoin heavy chain switches to B isoform (slower and economical contractor) cardiac hypertrophy: atrial natriuretic factor/peptide upregulated like in fetal life

muscle wasting. hint: sign of cancer

cachexia

if necrotic cells aren't eventually cleared, what does the body do?

calcify the area - dystrophic calcification

Physiologic apoptosis scenarios?

embryogenesis (between your fingers) involution of hormone dependent tissues cell loss in inappropriate proliferating cells (i.e. failure of B lymphocyte to express antigen receptors) elimination of self reactive lymphoctyes purposeful killing of inflammatory cells

example of physiologic atrophy

embryonic structures

What is the enyzme that causes this: 2O2* + 2H -> H2O2? Why would you want to create hydrogen peroxide?

enzyme: SOD (superoxide dismutase) Why H2O2: Because O2* is more damaging, and catalase converts hydrogen peroxide to water and oxygen.

the more a cell nears necrosis the more ________ they stain. Why?

eosinophilic loss of cytoplasmic RNA (basophilic) gain of denatured cytoplasmic proteins (eosinophilic)

where might you see a squamous to columnar metaplasia? what is this called?

esophagus Barrett esophagus

A microscope slide shows fragmented cells and amorphous granular debris enclosed within a distinctive inflammatory border. The person was known to have TB. What is the area of inflammation called where the cells encircle the area and form a new immune structure? what is the overall process?

granuloma caseous necrosis - cheese like

how can hyperplasia be stimulated?

growth factor- driven proliferation increased output of new cells from stem cells

what is another name for vacuolar degeneration? what is it?

hydropic change small clear vacuoles seen in cytoplasm representing distended and pinched off segments of ER *nonlethal

in what circumstances can hyperplasia not occur and only hypertrophy?

in permanent tissues: cardiac myocytes, skeletal muscle, nerves

what does IAP stand for? what does it do?

*I*nhibitors of *AP*optosis block caspases to keep cell alive

Jamie is a 300 lb female whose favorite past time is potato chips. She is starting to develop hypertension and as such her heart is receiving signals for hypertrophy. There are three steps for her heart to enlarge, one on the outside of the cell, one passing through the cell, and one in the center of the cell. What are the three signals that trigger her heart to hypertrophy?

1. Mechanical Stress (hypertension) 2. Vasoactive Agonists (signals that indicate work is coming) 3. Growth Factors (A signal that directly means to grow)

What are three ways that increased intracellular calcium leads to cell death?

1. Opens the Mitochondrial Permeability Transition Pore 2. Activates damaging enzymes such as phospholipase, protease, endonuclease, and ATPase 3. Induces apoptosis

What are the 4 mechanisms of increased damage due to reperfusion of an ischemic injury? What is this injury called?

1. Oxidative Stress: Reintroducing oxygen and nitrogen to damaged mitochondria further producing more ROS and RNOS 2. Calcium Overload: can get into cells easier from damaged membranes and triggers mitochondrial permeability pores 3. Inflammation: Ischemic tissue is ripe for leukocytes to attack and cause inflammation 4. Complement System: Just 'cause Name of disorder: Ischemia-reperfusion injury

What are the 4 general signs of reversible cell injury? What are the causes of these signs? What are the ultrastructural changes?

1. Swelling: No ATP, No Na/K pump, increased intracellular Na 2. Blebbing: damaged membrane and cytoskeleton 3. detachment of ribosomes from rough ER: decreased protein synthesis 4. clumping of nuclear chromatin: DNA damage 1. plasma membrane alterations (which cause blebbing) 2. mitochondrial swelling/densities 3. ER dilation with detachment of ribosomes 4. nuclear alterations

what is an apoptosome? how does it form? what does it do?

Apoptosome: hexamer formed by combining cytochrome c and Apaf-1(apoptosis activating factor). Form and Do: binds caspase 9 leading to auto-amplification

A cell is sitting at the tip of your big toe and because of a sedentary lifestyle it is not getting enough nutrients. Because of this low nutrient environment, what does the cell do when hungry?

Autophagy (self eating)

what happens to myelin figures if they are not phagocytized?

broken down into fatty acids which may be calcified into calcium soaps

a young aspiring pathologist has a slide of necrotic cells and wants to know why they have a more glassy homogenous appearance. what do you tell him?

1. pathology is for weirdos 2. it is because of the loss of glycogen particles

a man's coronary circulation is completely occluded. how much time do you have to save him before his heart stops beating?

60 seconds

what does bcl2 stand for? what does it do?

B-cell lymphoma (AKA "*B*e*C*ause I want to *L*ive" anti- apoptotic protein preventing membrane leakage via regulation of mitochondrial apoptotic protein release

mechanism of pro-apoptotic regulatory proteins and which ones are they?

BAX and BAK promote membrane permeability of apoptotic items i.e. cytochrome c

mechanism of anti-apoptotic regulatory proteins and which ones are they? what stimulates their expression?

BCL2, BCL-XL, MCL1 4 BH domains in outer mitochondrial and ER membranes prevent permeability of cytochrome c and other death-inducing proteins in healthy cell state growth factors and survival signals

3 causes of oxygen depravation?

Blood loss inadequate oxygenation reduced blood flow

In what tissues can coagulative necrosis not occur?

Brain, it can occur in every other tissue

what was the model organism for apoptosis studies?

C. elegans

Drugs that convert to toxic metabolites in liver?

CCl4 -> CCl3 deregulates lipid transport/export by causing ribosomes to hop off the ER, no lipoproteins synthesized with defective ribosomes so no apolipoproteins acetaminophen -> NAPQI

There was a blood clot blocking a small piece of tissue in your leg. After biopsy, you find a white hard substance in this area after the clot. What happened here?

Cell death (Calcium is often depositied at sites of cell death)

What is the term for a type of necrosis where the architecture of the dead tissue is preserved for a span of some days?

Coagulative Necrosis

A older gentleman presents with formation of bone in his muscle. after panicking, you examine further to find that he has had intramuscular hemorrhage. What is this classified as? what is the diagnosis?

Connective tissue metaplasia Myositis ossificans

what is a caspase? (i.e. how is the name derived?)

Cysteine protease=C that cleave= ASE after ASPartate residues= ASP C-ASP-ASE

causes of pathologic apoptosis

DNA damage Accumulation of misfolded proteins Certain infections (mainly viral) Pathologic atrophy in parenchymal organs after duct obstruction-> atrophy of organ

To put it all together, what is the process of apoptosis from DNA damage through the mitochondrial/intrinsic pathway to the execution phase of apoptosis (but not through that phase)?

DNA damage -> BIM, BID, and BAD, also known as BH3-only (*B*e*H*old the *only 3* who can foresee our death) sense the damage -> BH3-only proteins activate BAK/BAX ("Stab in the BAK with an AX) -> BAK/BAX insert into the mitochondrial membrane and leak out molecules (mainly cytochrome c) into the cytoplasm -> cytochrome c binds to APAF-1 -> these new love birds join with other love birds to make an apoptosome -> the apoptosome binds to caspase-9 -> caspase-9 activates other pro-caspases -> Execution phase

Jeremy, a 322 lb male, has renal stenosis of his right renal artery due to atherosclerosis. Upon CT exam, you find that his right kidney is smaller than his left. What type of atrophy is this?

Diminished Blood Supply Atrophy

Kristal has noticed that her menstrual periods are more intense in their bleeding. She sees the doctor to find that her estrogen levels are fine, but her progesterone levels are low. What type of disorder could this cause? What type of change in cells would this be known as?

Disorder: Endometrial Hyperplasia - progesterone inhibits proliferative endometrium Change: Pathologic hyperplasia

what is reduced in an atrophic muscle cell?

ER Mitochondria Myofilaments

where might you see hypertrophy after treatment with "toxic" drugs?

ER in hepatocytes (due to an increase demand/ supply of CYP450 enzyme)- patient will eventually respond less to drug = resistance

What is the process of apoptosis through the extrinsic pathway to the execution phase of apoptosis (but not through the execution phase)?

FasL binds to fas -> 3+ Fas are brought together -> Many Fas together form a death domain -> their cytosolic "death domain" binds to FADD (Fas associated death domain) -> FADD binds to inactive caspase 8 -> many inactive caspase 8's activate each other -> active caspase 8 -> activated caspase 8 activate executioner caspases

What is the type of necrosis seen in blood vessels where antigen/antibody complexes are deposited in the walls of the arteries?

Fibrinoid Necrosis

What is the type of coagulative necrosis that involves many tissue planes? When bacterial infection is superimposed, what is this called?

Gangrenous Necrosis Wet gangrene

Write the Fenton Reaction. What form must Fe be in to participate? What does this do for the body? How do you regenerate active form?

H2O2+ Fe2+> Fe3+ + 2(OH-) Fe2+ ferrous form accept/donate free electrons around the body O2*- can enhance regeneration of Fe3+ to Fe2+

In some forms of reversible injury there appears vacuoles in the cytoplasm. What type of injury causes this? What in the cell causes these vacuoles? What's in the vacuoles?

Hypoxic injury ER distends and pinches off (clear appearance) sometimes lipids are in the vacuoles with fatty change

This antibody has a propensity to deposit in Ischemic tissues?

IgM (part of the complement system ischemia-reperfusion injury)

This is a reflection of the oxidative state of the cell and is an important indicator of a cell's ability to detoxify ROS?

Intracellular ration of oxidized glutathione (GSSG) to reduced glutathione (GSH)

How is mercury toxic to the cells?

It is directly toxic and binds to cell membrane proteins and increases permeability of the cell and inhibits ion transport. This is very damaging to cells that want to concentrate ions such as GI and kidney cells.

What inside the cell causes necrosis?

Lysosomal enzymes enter the cytoplasm due to damaged membranes and eats the cell from the inside out and leads to inflammation

What is the type of connective tissue metaplasia that has bone formation in muscle usually due to intramuscular hemorrhage?

Myositis Ossificans

Necrosis vs. Apoptosis: Plasma Membrane

N- Disrupted A- Intact; altered structure, especially orientation of lipids

Necrosis vs. Apoptosis: Cell size

N- enlarged (swelling) A- reduced (shrinkage)

Necrosis vs. Apoptosis: Adjacent Inflammation

N- frequent A- No

Necrosis vs. Apoptosis: Physiologic or pathologic

N- pathologic A- often physiologic. can be pathologic (ex DNA damage)

Necrosis vs. Apoptosis: Nucleus

N- pyknosis>karyorrhexis>karyolysis A- fragmentation into nucleosome-size fragments

Necrosis vs. Apoptosis: Cellular contents

N-Enzymatic digestion; may leak out of cell A- Intact; may be released into apoptotic bodies

How does decreased ATP due to hypoxia cause and increase in intracellular Ca?

No ATP -> Increased Intracellular Na and decreased extracellular Na -> No Ca/Na transporter

How does decreased ATP due to hypoxia cause a decreased pH in the cell and a decrease in enzymes and proteins?

No ATP -> increased AMP -> activates phosphofructokinase -> activates anaerobic glycolysis -> accumulation of lactic acid -> low pH -> decreased activity of enzymes

How does decreased ATP due to hypoxia cause decreased protein synthesis?

No ATP -> increased AMP -> activates phosphofructokinase -> activates anaerobic glycolysis -> accumulation of lactic acid -> low pH -> decreased activity of enzymes including Ribosomes

How does decreased ATP due to hypoxia cause decreased glycogen store?

No ATP -> increased AMP -> activates phosphofructokinase -> activates anaerobic glycolysis -> destruction of glycogen for glucose

How does decreased ATP due to hypoxia cause the unfolded protein response which leads to cell injury/death?

No ATP -> increased AMP -> activates phosphofructokinase -> activates anaerobic glycolysis -> destruction of glycogen for glucose -> no glucose + no oxygen leads to misfolded proteins -> unfolded protein response

how does decreased ATP due to hypoxia cause cell swelling?

No ATP -> no Na/K pump -> Increased intracellular Na -> Increased Osmolarity -> more water in cell (swelling)

HIF-1 (hypoxia-inducible factor) protects against hypoxic stress. how does it do that?

Promotes new blood vessel formation stimulates cell survival pathways enhances anaerobic glycolysis

how does cyclosporin work to prevent cell death?

blocks cyclophilin D, which is part of the mitochondrial permeability transition pore, which prevents its opening. this maintains membrane potential

Infarction has just occurred in the heart and some of the myocardiocytes are damaged beyond repair. You immediate take out some of the cells and put them under a microscope. What are you going to see that is different from normal cells compared to these necrotic cells? Why? When will changes to this look occur?

See: Nothing, they look the same Why: Digestion of the cell takes hours When: 4-12 hours later is when you will see necrotic changes.

What is the process known as when cells degrade their own organelles for nutrients and to decrease metabolic load? How can you tell that this is happening microscopically?

Self-eating: Autophagy Microscopically: Autophagic Vacuoles

Penelope is an 88-year-old female who was brought in by her family for neuro problems where she is loosing her memory and has a lower functioning capacity. You do an MRI to find that her sulci in her brain are increased. You also hear some bruits in her carotids and assume they are atherosclerotic. What specific type of Diminished Blood Supply Atrophy is this?

Senile Atrophy: atrophy of the brain due to reduced blood supply

Jamie is a 300 lb female whose favorite past time is potato chips. She is starting to develop hypertension and as such her heart is receiving signals for hypertrophy. There are three steps for her heart to enlarge, one on the outside of the cell, one passing through the cell, and one in the center of the cell. The heart has been triggered to hypertrophy from the receptors on the outside of the cell. What's next?

Signal Transduction through the cell. This is done through: PI3K/AKT pathway (phosphoinositide 3-kinase) GPCR stimulation transcription factor's that were activated do their thing (GATA4, NFAT, MEF2) to increase muscle protein synthesis

What happens to an adapted cell once the stressor is removed?

The cell can recover to its original state.

A patient presents with a deficiency of Vitamin A. What changes might happen to epithelial cells? where? How?

What: squamous metaplasia Where: respiratory epithelium How: Retinoic acid (A) regulates gene transcription directly through nuclear retinoid receptors

Why does coagulative necrosis keep the original architecture of the dead tissue? what's the name for the area of coagulative necrosis?

The injury denatures proteins and enzymes so proteolysis of the dead cells can't occur infarct

what do BIM, BID, and BAD do? what do they activate?

They sense: DNA/cellular damage stress misfolded proteins They Activate: bax and bak that form a channel in the membrane. also block survival signals (bcl) ("They stab the mitochondria in the *BAK* with an *AX* (BAX))

True or False: Julie hasn't received any signals to increase the size of her uterus, therefore atrophy sets in and the size of the uterus begins to decrease. This is due to a decrease in the size of the cells.

True, but atrophy is both a decrease in the size and number of cells.

Catalyzes this reaction: 2H2O2> O2 + 2H2O. where is it found?

catalase peroxisomes

how can mitochondrial damage induce apoptosis?

cytochrome c released during damage indirectly activates capsases

how is the intrinsic (Mitochondrial) pathway initiated?

increased mitochondrial permeability causes release of cytochrome c into cytoplasm

These metals can catalyze the formation of ROS. how do you minimize this?

iron copper bind them to proteins

characteristics of irreversible cell injury

irreversible mitochondrial functions profound membrane disturbance especially lysosomes

difference between tissues experiencing ischemia vs. hypoxia

ischemic tissues will not be able to undergo anaerobic glycolysis because it is not getting the substrates. this makes the condition more rapid and severe than hypoxia

define the following terms that apply to nuclear changes due to necrosis: Karyolysis Pyknosis Karyorrhexis what order do they usually occur in?

karyolysis: fading of the basophilia of chromatin - disolution of nucleus pyknosis: nuclear shrinkage and increased basophilia karyorrhexis: pyknotic nucleus undergoes fragmentation pyknosis -> karyorrhexis -> karyolysis

How do free radicals attack cell membranes?

lipid peroxidation OH radical attacks double bonds and propagates extensive membrane damage

Pus presented cell death due to infection or hypoxia of the CNS is called __________ what's the mechanism of this?

liquefactive necrosis digestion of dead cells with enzymatic release and infiltration of leukocytes manifests conglomerate of pus

In the presence of oxygen but mitochondrial damage, how might oxidative phosphorylation fail?

loss of mitochondrial membrane potential via mitochondrial permeability transition pore which leads to a decrease in the mitochondrial membrane potential.

profound protein-calorie malnutrition

marasmus

what is the cell's response to chronic irritation?

metaplasia

The reversible change in which one differentiated cell type is replaced by another? What is the most common form of this change?

metaplasia columnar to squamous (i.e. in respiratory tract from chronic irritation- SMOKING)

what is the major pathway for apoptosis in mammalian cells?

mitochondrial (intrinsic) pathway

example of residual bodies left over from autophagy?

neuron poop (lipofuscin)

predominant cells that produces ROS?

neutrophils and macrophages

ROS generated by addition of one electron two electrons three electrons and the antioxidant rxns that mediate each?

one electron = superoxide O2*- SOD - superoxide dismutase two electrons = H2O2 catalase, sometimes glutathione peroxidase three electrons = hydroxyl ions OH* glutathione peroxidase

how do free radicals modify proteins?

oxidative modification oxidation of AA side chains also formation of cross linkages i.e. disulfide bonds

what does CYanide affect?

poisons CYtochome oxidazes- blocks oxidative phosphorylation in the mitochondria

fat + calcium = ? when would this occur?

saponification fat necrosis i.e. pancreatitis release of lipases

what do you expect to see morphologically from a cell undergoing apoptosis

small cells (A) condense chromatin (B) cytoplasmic blebs/apoptotic bodies (C) phygocytosis of apoptotic bodies *cytoplasm will be eosinophilic

how do macrophages recognize that the cell is dead?

specific phospholipids (phosphatidylserine) move from the inner leaflet to the outer This is recognized by annexin V and by phagocyte receptors

how does pathologic hyperplasia differ from cancer?

there is no genetic mutation therfore regulation is intact. This does, however, put the individual at a greater risk for developing cancer

what do free fatty acids, acyl carnitine and lysophospholipids have in common? what do they do?

they are phospholipid breakdown products for phospholipase which is activated by intracellular Ca. They have a detergent effect on membranes and damage the membranes

mechanism of atrophy?

ubiquitin marks proteins for degradation via proteosomes

example of hormone-induced hypertrophy

uterus during preggerosity

what are myelin figures? when would you see them?

whorled phospholipid masses from damaged cell membranes seen in necrosis