Cell injury/death Flashcards by Lydia Payton

What are some causes of cell injury?

Ischemia
Physical agents
Chemical agents
Infectious agents
Immune reactions
Genetic abnormalities
Nutritional imbalances
Aging

How well did you know this?

Not at all

Perfectly

Where are sites within the cell that vulnerable/lead to injury?

Mitochondria
Membranes
Ribosomes
Cytoskeleton
Genome

How well did you know this?

Not at all

Perfectly

What are some common mechanisms of injury to the cell?

ATP depletion
Elevated cytosolic Ca2+  ***
Oxidative stress
Loss of membrane integrity
Protein misfolding
DNA damage

How well did you know this?

Not at all

Perfectly

ATP depletion leads to….

ex.s of relevant situations?

Mitochondrial oxidative phosphorylation
Anaerobic glycolysis

Ischemia - restriction in blood supply to a tissue
(Shortage of oxygen and glucose)

Chemical damage to mitochondria
(Toxins, drugs)

How well did you know this?

Not at all

Perfectly

What is the outcome of ATP depletion as it relates to transporters?

**important

Failure of the Na+/K+ pump

(Na+diffuses in, K+ diffuses out)

NET GAIN OF SOLUTE! - the cell takes on water… osmotic swelling or hydropic change!!

How well did you know this?

Not at all

Perfectly

What is the outcome of ATP depletion for translation/energy production? (2)

**important

Translational machinery fails:

Ribosomes detach from the ER and polysomes dissociate
Protein synthesis declines!!!!

Compensatory shift to glycolysis:

↓ pH (lactic acid accumulation)
Enzyme function declines (pH sensitive)

How well did you know this?

Not at all

Perfectly

What are two sources of elevated cytosolic Ca2+?

extracellular - failure of pm Ca2+ ATPase ( pumps it out)

internal stores - damge to mitochondria and ER as a result

How well did you know this?

Not at all

Perfectly

What are the consequences of elevated cytosolic Ca2+? (2)

Activation of enzymes that are calcium dependent (phospholipases, proteases, endonucleases, ATPases for ex)

Altered mitochondrial membrane potential

How well did you know this?

Not at all

Perfectly

When is ROS commonly encountered in cells?

Byproduct of normal metabolism 
Ionizing radiation
Inflammatory cell oxidative burst
Drug metabolism
Iron toxicity
Chemical signaling via nitric oxide

How well did you know this?

Not at all

Perfectly

Why does oxidative stress occur?

imbalance between ROS and ROS scavenging systems

**ROS = superoxide 02-, hydrogen peroxide (h2o2), hydroxyl radical (Oh-)

How well did you know this?

Not at all

Perfectly

What are some examples ROS scavengers?

Vitamens C and E (antioxidant activity)

Enzymes: superoxide dismutase, catalase, glutathione peroxidase

How well did you know this?

Not at all

Perfectly

What would lead to a loss of membrane integrity?

Reduced phospholipid synthesis (ATP depletion)

Increased phospholipase activity (Ca2+ influx)

Increased protease activity (Ca2+ influx)
- Disrupts the membrane-associated cytoskeleton

**vulnerable targets: PM, mitochondria, lysosomes, ER

How well did you know this?

Not at all

Perfectly

Why does protein misfolding occur?

ATP decline increases it

activates the unfolded protein response (UPR)

purpose: increase ER protein folding capacity/degrade any terminally misfolded proteins
if unresolved: triggers apoptosis!!

How well did you know this?

Not at all

Perfectly

If there is no stress in the cell… p53 transcription factor is…

unstable due to ubiquitination (targeted to proteasome)

How well did you know this?

Not at all

Perfectly

If there is DNA damage, it activates a DNA damage checkpoint and p53…

is stabilized! (due to phosphorylation, reduced ubiquitination)

stress is resolved or there is apoptosis

How well did you know this?

Not at all

Perfectly

Free p53: low levels in the absence of DNA damage

DNA damage: complex is phosphorylated, ubiquitination declines, free p53 accumulates – cell cycle arrest, dna repair activated

…

How well did you know this?

Not at all

Perfectly

P53 – engineered to kill cell if it cannot repair the DNA damage!

…

How well did you know this?

Not at all

Perfectly

Necrosis is mostly…

pathologic!

damage to a cell exceeds repair capacity
viral infection, toxins, ischemic injury

How well did you know this?

Not at all

Perfectly

what are some exs of physiologic necrosis?

ischemia of uterine lining during menstruation

How well did you know this?

Not at all

Perfectly

What are the general features of necrosis

ENERGY FAILURE!!

1) cells swell (hydropic change)
2) membranes leak - inflammation is triggered
3) nuclear destruction
- pyknosis
- karyorrhexis
- karyolysis

How well did you know this?

Not at all

Perfectly

pyknosis

shrinkage

How well did you know this?

Not at all

Perfectly

karyorrhexis

fragmentation

How well did you know this?

Not at all

Perfectly

karyolysis

dissolution/dissolve of membrane

How well did you know this?

Not at all

Perfectly

necrotic cells trigger inflammation

…

How well did you know this?

Not at all

Perfectly

there is a fine balance between protein denaturation and enzymatic digestion...

...

if protein denaturation exceeds enzymatic digestion, what occurs?

coagulative necrosis

what are some common causes of coagulative necrosis?

thrombus air/fat embolus (surgery) tumor cells

what is the pathology of coagulative necrosis? gross and microscopic

gross: tissue is firm microscopic: cell outlines ('ghosts') are preserved (for a while) - but those cells are dead so eventually will fall apart

look at picture of coagulative necrosis renal infarct! **loss of cellular detail!

karyolysis can also indicate basophilic nuclei being gone

....

if enzymatic digestion exceeds protein denaturation, what occurs?

liquefactive necrosis

in liquefactive necrosis, what happens to the tissue? two exs? gross/microscopic?

tissue becomes a viscous mass!! - ex. tissue abscess (focused infection) - microbes AND inflamm cells release hydrolytic enzymes - ex. of noninfectious liquefactive is cerebral infarction (focal loss of blood supply with stroke; neurons die and become soft and wet) gross: tissue becomes soft and 'wet' microscopic: lots of PMNs and cell debris (few cellular details)

what type of cell dominates in liquefactive?

neutrophils!!

picture of liquefactive necrosis - CNS - brain is "shiny" after that tissue goes away, there will be a cavity where the necrosis occured

...

liquefactive microscopic: lack of nuclei surrounded by PMNs little cellular debris lots of eosinophilia

....

caseous necrosis... gross appearance? classic ex?

dead tissue appears as white, soft, cheesy-looking material ("caseous") ex. tuberculosis

how is Tb transmitted? what is the host response? problem?

inhaled phagocytksed by alveolar macrophages Tb evades killing so the solution is to contain the infection in a GRANULOMA.

What does a granuloma look like at the microscopic level?

central core: Tb infected macrphages ``` periphery: Foamy macrophages (accum lipid) Epithelioid macrophages (look like epi cells – really angry) Giant cells (fused macrophages) Lymphocytes ```

Foamy macrophages – accumulate lipid - evidence that Mtb may induce their formation to their own benefit – nutrition epitheliod macrophages are activated

...

progressive central necrosis in granulomas is bad because...

signals waning containment

What is fat necrosis?

Focal destruction of fat Not considered a specific pattern of necrosis

What is fat necrosis characteristic of?

acute pancreatitis! Drugs/alcohol, trauma, infection Pancreatic damage releases lipases & other enzymes into the pancreas and peritoneal cavity

What is the gross appearance of fat necrosis?

Fat deposits in greater omentum (lots of fat in it) digested by lipases released from injured pancreas Free fatty acids combine with calcium (saponification) – white, chalky deposits **sign of damage to pancreas

see microscopic slide of what fat necrosis looks like/parenchymal necrosis

What is gangrenous necrosis?

widely used term clinically not considered a distinct form of necrosis.. can be dry or wet

what is dry gangrene?

ischemia, usually of distal limb damage is COAGULATIVE NECROSIS!!

what is wet gangrene?

dry gangrene superimposed bacterial infection: LIQUEFACTIVE NECROSIS

what is gas gangrene?

Deadly form of wet gangrene associated with crepitus (ability to hear gas under skin) Anaerobic bacteria that produce potent toxins (claustridium perfringes, etc)

Apoptosis = programmed cell death.. | it is a physiological response to?

sub-lethal damage external signals

What are the two pathways for apoptosis?

Intrinsic: mitochondria-dependent - Mechanism: Cytochrome C release activates caspase cascade - Triggers: Direct: damage to mitochondria (release cytochrome C) Indirect: regulated mitochondrial permeability via bcl-2 proteins!! Extrinsic: membrane receptor-mediated (Fas, TNFR – tumor necrosis factor receptor) - Adaptor proteins trigger caspase activation

Apoptosis - goes int o blebs - apoptotic bodies expose phosphatidylserine on surface!! - recognized by phagocytic cells and eaten

...

Direct damage to mitochondria, or indirect regulation of mitoch. perm through bcl-2 family members Variations exist but not important here: necroptosis - uses diff adaptors, not casp dep - tnf Pyroptosis – microbe infected cells – involves active of inflammasome

Phag. Of apop cells can trigger the release of cytokines that downplay inflamm. If apoptotic cells are not cleared rapidly, they will proceed into necrosis

...

Difference between necrosis vs apoptosis: Necrosis – leakage of cell is key – get inflamm response Apoptotic cell – recognized bc expose phophatidylserine – easily recognized as abnormal – doesn’t bring in neutrophils – not in flammatory!! - Reason for this is bc apoptotic pathway is happening all the time!!

...

Apoptotic cells are happening all the time - cleared rapidly without inflammation

...

Microscopically... look at apoptotic cells!

...

What is the clinical importance of apoptosis in neurodegenerative disease?

Protein misfolding disorders overwhelm mechanisms of proteostasis (Alzheimer’s, Huntington’s, Parkinson’s) Apoptosis contributes to degeneration UPR is one mediator

What is the clinical importance of apoptosis in infectious disease?

Infection by intracellular pathogens | Apoptosis kills the cell

What is the clinical importance of apoptosis in carcinogenesis?

Normal cells: genotoxic damage activates p53 (Tumor suppressor role: if repair fails - apoptosis) Cancer cells: p53 is abnormal Damaged cells fail to die

What is the clinical importance of apoptosis in cancer therapy?

Apoptosis induction: radiation, chemotherapy, hormone ablation therapy

Many new drug targets for pro and anti apoptotic pathways

...

Summary of necrosis...

Injury exceeds repair Mostly pathologic Death - energy failure Morphology: Cells swell Membranes leak Inflammatory response: Strong

Summary of apoptosis?

Programmed death Physiologic or pathologic Death: caspase activity Morphology Cells fragment - apoptotic bodies Membranes remain intact Inflammatory response: Minimal

coagulative necrosis looks like the white area of muscle on slide..

...

Hypoxia summary?

Inadequate O2 (Anemia or Displacement of O2 from erythrocytes) May or may not be associated with ischemia

Ischemia summary?

Restricted blood flow: - Hypoxia - Impaired delivery & removal of metabolites - Injury is more potent than hypoxia alone

What triggers atheroschlerosis/ ischemic heart disease?

endothelial damage!! high cholesterol/cigarettes lipoproteins accumulate in the vessel wall.... - triggers a cycle of chronic inflammation: - Macrophages influx/death/more recruitment - Smooth muscle cell proliferation - Cell death: accumulation of necrotic debris (plaque)

what is an atheroma?

accumulation of plaque

dystrophic calcification stiffens the plaque (becomes fragile) plaque ruptures.. platelets activated, thrombus forms, ischemic injury to downstream tissue!!

What is the mechanism of ischemia-reperfusion injury?

Increased ROS generation (sudden influx of O2 to hypoxic tissue and sudden influx of inflamm cells) complement binds to ischemic tissues!!

outcome of ischemic injury?

Early injury - reversible Sustained injury – irreversible: - Coagulative necrosis of ischemic tissues - Apoptosis of surviving, but damaged cells

Cell injury/death Flashcards

(71 cards)