Cellular Injury and Adaptation Flashcards by Uche PM

In response to a cancer caused by the PML-RAR-alpha fusion gene which leads to disseminared intravascular coagulation, what is an accepted drug treatment?

ATRA - All trans retinoic acid

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Causes of cell injury can be instrinsic or _. Examples of _ are hypoxia/ischemia, physical, chemical, immunilogic, nutiritional and infection

Acquired

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What is thought to happen to cells when an injury is mild and transient? What is though to happen when the injury is severe and progressive?

Reversible injury, back to normal

Irreversible injury, eventually leading to cell death

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What are the 2 major types of cell death?

Necrosis and apoptosis

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Arrange the following events in the order that they occur

Gross morphiological changes
Ultrastructural changes
Biochemical alterations
Changes visible by light microscopy

Biochem - > Ultrastructural -> Light changes -> Gross morphological changes

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What type of conditions have to be met for morphological changes to be visible under a light microsopy? (i.e. what type of injury)

Prolonged and severe injury

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What is the difference between atrophy, hypertrophy and hyperplasia?

Atrophy - loss of tissue / cell size
Hypertrophy - Increase in cell / organ size
Hyperplasia - increase in number of cells produced

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What is metaplasia?

Cells change their differentiation

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What are 4 sites of vulnerability regarding cell injury?

Membrane integrity
Aerobic respiration
Protein Synthesis
DNA integrity

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How can mitochondria contribute to cell injury / death?

When damaged, source of cytochrome C which activates caspases

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How can calcium influx contribute to cell death / injury?

It can increase mitochondrial permeability, increase activation / release of cytochrome C and caspases
Neurotoxicity

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Reduced ATP, Mitochondrial damafe, Increased calcium, ROS, Membrane damage and protein/DNA damage can all contribute to cell death. Which is the culprit in most cases?

Unclear, usually a combination of several of those factors

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What are 2 proteins that can be quantified in a patients blood following an MI due to membrane damage?

CK - MB

Troponin

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How does a mitochondrion respond to ischemic conditions? What product in reduced because of this response?

Reduced oxidative phosphorylation (no oxygen)

Reduced ATP made

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What type of cellular damage would cause the following when looking at mitochondria:

Reduced protein synthesis
Increased lipid deposition
Clumping of nuclear chromatin

Ischemia

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Regarding the following ions / molecules, what would you expect following mitochondrial damage due to ischemia?

Sodium pump
Calcium, water, sodium, potassium

Decreased pump activity
Influx - Calcium water and sodium
Efflux - Potassium

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What are 3 specific events that can lead to mitochondrial dysfunction?

Increased cytosolic calcium
Increased ROS (oxidative stress)
Lipid peroxidation

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Membrane integrity can affect whether mitochondria initiates apoptotic or necrotic mechanisms. Explain.

If both mitochondrial membranes are impaired (loss of membrane potential), you get necrosis
If only the outer membrane is impaired (Cyt C, other pro-apoptotic proteins), you get apoptois

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Prolonged increase in intracellular calcium levels can lead to cell death. What are 3 sources? What is the normal cytoplasmic level of calcium vs. extracellular levels?

Mitochondria
ER
Extracellular space
0.1 micromolar vs mM level extracell.

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What are 4 enzymes mentioned that are activated by calcium?

Phospholipase
Proteases
Endonucleases
ATPases

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What are the 4 free radicals / ROS molecules mentioned in the notes?

Superoxide radical
Hydrogen peroxide
Hydroxyl radical
Peroxynitrite anion

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Which ROS is made from 2 superoxide molecules? Which depends on water ratiation for its formation? Which is formed from an endogenous vasodilator?

Hydrogen peroxide
Hydroxyl radical
Peroxynitrite anion (nitric oxide)

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What is the enzyme used by immune cells to generate superoxide for killing bacteria? What disease develops if this enzyme in not functional?

NADPH oxidase

Chronic granulomatous disease

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Excess O2 (e.g oxygen therapy in COPD), inflammation and reperfusion following ischemia are all related to reactive oxygen species because _.

They are all potential sources of ROS.

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What is the enzyme in neutrophils that is thought to generate ROS following reperfusion?

Xanthine Oxidase

What is the enxyme within mitochondria that is able to generate hydrogen peroxide from superoxide? What type of reaction generates a hydroxyl radical from hydrogen peroxide? What is the necessary cofactor?

Superoxide dismutase Fenton reaction Hydroxyl radical (very reactive)

Which can cause injury: Too much ROS production or inadequate defense against ROS?

Both can cause injury

What are 2 antioxidant vitamins that have been used in drug trials to prevent ROS injury? (Few trials have shown benefit)q

Vitamin A | Vitamin E

In cases of acetaminophen toxicity, what molecule when free can cause severe liver injury? What molecule is normally present but can become depleted if too much acetaminophen is ingested? What can be used to treat people in cases of tylenol toxicity and what does it accomplish?

Free NAPQI Glutathione N-acetyl-cysteine

How are anoxia and asphyxia different?

Anoxia - lack of oxygen delivery | Asphyxia - Lack of oxygen from not breathing (a subtype)

Group A - Loss of ATP, glycogen depletion, reduced intracell pH, failure of membrane transport systems and detachment of ribosomes Group B - Membrange damage, intracell release of lysosomal enzymes, massive calcium influx Which of the 2 groups represent reversible damage? Which is irreversible?

Reversible - A | Irreversible - B

What might be obsevrved microscopically in response to reduced intracell pH? What about in response to membrane transport systems failure?

reduced pH - Clumping of nuclear chromatin | failure of transport - Edema

What are signs of loss of membrane integrity?

Phospholipase activation | Cytoskeletal abnormalities

Membrane blebs, loss of microvilli and mitochondrial swelling are all signs of _. Is this reversible or irreversible? What is the caveat?

Cell swelling | Reversible if early

Viral injury, DNA damage is likely to initiate apoptosis or necrosis?

Apoptosis (usually in response to intracellular injury)

True or false - necrosis is non-physiologic while apoptosis is physiologic?

False, apoptosis can be both physiologic and non-physiologic

What type of cell death is described as - requiring energy, new protein transcription, leave intact lysosomes and cell membranes?

Apoptosis

Cell death that involves karyolysis and karyorrhexis is likely _. What about chromatin clumping?

Necrosis Karyolysis - loss of nuclear staining Karyorrhexis - nuclear fragmentation Chromatin clumping is usually apoptosis

Inflammation is usually associate with what type of cell death?

Necrosis

Cell death that involves cell shrinking is likely _ which cell swelling is likely _

Shrink - apoptosis | Swelling - Necrosis

In necrosis, in what order to pyknosis, karyolysis and karyorrhexis occur?

Pyk - > karyrrhexis - > klysis

What enzyme is responsible for karyolysis?

DNase

What are 3 early changes associated with necrosis?

Hypereosinophilia Cytoplasmic vacuolization Nuclear changes

What are the 2 main types of necrosis?

Coagulation | Liquefaction

A necrosis where injury and acidification denatures proteins but blocks proteolysis is likely _ type of necrosis. The prototype of this is _. What is a hallmark of this process?

Coagulation MI Cell outlines and tissue structure is preserved

A necrosis where heterolysis is driven by extrinsic catalytic enxymes and loss of cell outlines and tissue structure is observed is _. What is the prototype?

Liquefactive necrosis | Bacterial absess

Beyond liquefaction and coagulative necrosis, what are 3 other types of necrosis?

Gangrenous, caseous and enzymatic fat necrosis

In coagulative necrosis (e.g. MI), what would you expect nuclei to look like?

Very faint, won't pick up stain

A typical example of caseous necrosis is _ while a typical example of enzymatic fat necrosis is _

TB | Pancreatitis

Long story short, necrosis where you preserve cell structure / out line is _, whole necrosis where the tissue structure is lost is _

Coagulative | Liquefactive

True or false, apoptosis is required for normal development?

True

What is a phospholipid that is usually expressed only inside a cell, and when expressed on the bilayer outer leaflet signals apoptosis?

Phosphotidylserine

What are 2 signaling kinases(?) mentioned in the notes that are important for apoptosis?

Bax and Bak

In clinical cases where necrotic cell death is an issue, what is the major goal of healthcare providers giving treatment?

To limit injury

How is apoptosis manipulated by viruses?

Viruses can block apoptotic proteins to promote viral replication and spread (buy time)

In the lecture, what 2 proteins were mentioned as abberant in cancers? Are the upregulated or down regulated?

Bcl2 expression assoc. with cancer | Loss of P53 assoc. with cancer

True or false, apoptosis is involved in both ischemic and neurodegerative cell death?

That is the current hypothesis, not completely clear

What version of caspase 3 is found in all cells? What version is responsible for apoptosis?

Inactive caspase 3 in all cells | Activated / cleaved caspase 3 involved in apoptosis

When looking at a microscopic field containing cells dying, how would these cells be arranged if undergoing apoptosis? What about necrosis?

Apoptosis - randomly dying cells interspersed with live cells Necrosis - Probably all cells dying will be next to each other

Why is there more apoptosis associated with malignancy?

Because the rapidly dividing cells are likely to generate non-viable mutations that lead to cell death

What is intrinsic apoptosis? What is a key step in this process? What is the major protein family members that control this process?

Apoptosis initiated from within Mitochondrial permeabilization Bcl-2 family members

What is extrinsic apoptosis? Where are the initiating proteins located? What are 3 examples of these proteins?

Apoptosis initiated from outside On the cell surface Fas, TNF, Trail

What is the step where the extrinsic and intrinsic apoptotic pathways usually converge? What is the protein at that step?

At the step of the executioner caspases | Caspase 3

Caspase inhibitors have been pursued as drugs to block apoptosis. These drugs are likely to block only extrinsic but not intrinsic apoptosis. Why?

By the time the intrinsic pathway gets to the caspase 3 step, the mitochondrial membrane is already compromised. No turning back from that.

What are the effector proteins of the Bcl-2 family of proteins? What do they do?

Bax and Bak | Form a pore that releases cytochrome C from the intermembrane space of the mitochondria

Bcl-2 has pro and anti-apoptotic family members. How do the antiapoptotic family members interact with Bax and Bak?

The can block the formation of the pore that releases cytochrome C

What are the 2 executioner caspases?

Caspase 3 and caspase 7

What type of cell death are the FasL/Receptor involved in? In what disease are they defective in? What is this disease?

- Extrinsic apoptosis - Defective in Autoimmune Lympho Proliferative Syndrome - Defects in extrinsic apoptosis results in increased lymphocyte survival and autoimmunity

What drugs were developed (Attempted) to prevent apoptosis in ischemic injury? What drugs were developed (attempted) to facilitate apoptosis in cancer (2)?

Caspase inhibitors for ischemic injury | Bcl2 antagonists and death receptor agonists

Whether pro or anti-apoptotic, what is the domain shared by all Bcl-2 proteins?

BH3

What are Bcl2 antagonists expected to do in cancer?

Antagonism of Bcl-2 should lead to increased apoptotic cell death

Why are majority of the Bcl2 antagonists not used clinically (not FDA approved)?

Cause major thrombocytopenia because the inhibit platelets

How may autophagy be related to cancer? How may autophagy help in neurodegenerative disease?

Thought that defects In autophagy lead to cancer | Think that autophagy can help remove misfolded proteins that accumulate in neurodegenerative disease

Where are the proteins PINK1, PARL and Parkin found? What are their functions?

Found in and around mitochondria PINK1 - imported into health mitochondria, can recruit Parkin PARL - Degrades PINK1, prevents recruitment of Parkin Parkin - Initiates mitophagy when recruited by Pink1

Under what conditions might Pink1 accumulate in the outer mitochondrial membrane where it can recruit Parkin? What will Parkin initiate? In what disease are Pink1 and Parkin defective?

Following loss of mitochondrial transmembrane potential Parkin initiates mitophagy Early onset Parkinson

Intracellular accumulation can cause cellular injury. What are 3 normal cellular components that accumulate and cause cell injury?

Triglycerides (Fatty liver) Protein droplets Glycogen

Intracellular accumulation can cause cellular injury. What is an example of a disease associated with accumulation of abnormal substances?

Lysosomal storage disease

Intracellular accumulation can cause cellular injury. What are 3 examples of pigments that accumulate and cause disease?

Carbon / coal dust Malanin Hemosiderin

What are the 4 mechanisms by which intracellular accumulation can occur?

* abnormal metabolism * abnormal protein folding or transport * genetic enyzmatic defect * incomplete lysosomal degradation

Misfolded protein accumulation is mainly associated with what type of disease? What are 5 examples provided?

``` Neurological disease •Amyloidosis •Alpha 1 anti-trypsin •Alzheimer’s •Huntington’s •Parkinson’s ```

What are 3 factors that make neurons succeptible to injury from protein folding?

Large size Inability to divide Defective proteins accumulate over decades

An example of a disease where lipid accumulation is a problem is _. What process is abnormal?

Fatty liver disease | Lipid metabolism

What are foam cells? What disease are they implicated in?

Cholesterol in macrophages | Atherosclerosis

What disease is associated with a deficiency in myophosphorylase (alpha- 1,4-glucan orthophosphate glycosyl transferase)? What molecule abnormally accumulates and where?

McArdle's disease | Glycogen in skeletal muscle

What disease is associated with high iron accumulation in the liver? What is the name of these deposits? How is this treated? How is the disease now detected?

Hemachromatosis Hemosiderin Phlebotomy Genetic test from blood sample

Nuclear fragmentation is more likely to be associated with necrosis or apoptosis?

Necrosis

``` Which of the following doesn't function to limit ROS damage? superoxide dismutase NADPH Oxidase catalase Glutathione Peroxidase Vitamin E ```

NADPH oxidase, because it actually creates ROS to kill bacteria. SOD tempting because it make H2O2, but it is making it from a more reactive species

Cellular Injury and Adaptation Flashcards

(87 cards)