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Cellular Week 4 > Cell injury/death > Flashcards

Cell injury/death Flashcards

1
Q

What are some causes of cell injury?

A 
Ischemia
Physical agents
Chemical agents
Infectious agents
Immune reactions
Genetic abnormalities
Nutritional imbalances
Aging
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2
Q

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

A 
Mitochondria
Membranes
Ribosomes
Cytoskeleton
Genome
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3
Q

What are some common mechanisms of injury to the cell?

A 
ATP depletion
Elevated cytosolic Ca2+  ***
Oxidative stress
Loss of membrane integrity
Protein misfolding
DNA damage
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4
Q

ATP depletion leads to….

ex.s of relevant situations?

A

Mitochondrial oxidative phosphorylation
Anaerobic glycolysis

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

Chemical damage to mitochondria
(Toxins, drugs)

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5
Q

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

**important

A

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!!

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6
Q

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

**important

A

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)
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7
Q

What are two sources of elevated cytosolic Ca2+?

A

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

internal stores - damge to mitochondria and ER as a result

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8
Q

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

A

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

Altered mitochondrial membrane potential

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9
Q

When is ROS commonly encountered in cells?

A 
Byproduct of normal metabolism 
Ionizing radiation
Inflammatory cell oxidative burst
Drug metabolism
Iron toxicity
Chemical signaling via nitric oxide
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10
Q

Why does oxidative stress occur?

A

imbalance between ROS and ROS scavenging systems

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

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11
Q

What are some examples ROS scavengers?

A

Vitamens C and E (antioxidant activity)

Enzymes: superoxide dismutase, catalase, glutathione peroxidase

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12
Q

What would lead to a loss of membrane integrity?

A

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

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13
Q

Why does protein misfolding occur?

A

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!!
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14
Q

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

A

unstable due to ubiquitination (targeted to proteasome)

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15
Q

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

A

is stabilized! (due to phosphorylation, reduced ubiquitination)

stress is resolved or there is apoptosis

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16
Q

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

A

…

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17
Q

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

A

…

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18
Q

Necrosis is mostly…

A

pathologic!

  • damage to a cell exceeds repair capacity
  • viral infection, toxins, ischemic injury
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19
Q

what are some exs of physiologic necrosis?

A

ischemia of uterine lining during menstruation

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20
Q

What are the general features of necrosis

A

ENERGY FAILURE!!

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

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21
Q

pyknosis

A

shrinkage

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22
Q

karyorrhexis

A

fragmentation

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23
Q

karyolysis

A

dissolution/dissolve of membrane

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24
Q

necrotic cells trigger inflammation

A

…

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25
Q

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

A

…

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26
Q

if protein denaturation exceeds enzymatic digestion, what occurs?

A

coagulative necrosis

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27
Q

what are some common causes of coagulative necrosis?

A

thrombus
air/fat embolus (surgery)
tumor cells

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28
Q

what is the pathology of coagulative necrosis?

gross and microscopic

A

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

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29
Q

look at picture of coagulative necrosis renal infarct!

**loss of cellular detail!

A

..

30
Q

karyolysis can also indicate basophilic nuclei being gone

A

….

31
Q

if enzymatic digestion exceeds protein denaturation, what occurs?

A

liquefactive necrosis

32
Q

in liquefactive necrosis, what happens to the tissue?

two exs?
gross/microscopic?

A

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)

33
Q

what type of cell dominates in liquefactive?

A

neutrophils!!

34
Q

picture of liquefactive necrosis - CNS - brain is “shiny”

after that tissue goes away, there will be a cavity where the necrosis occured

A

…

35
Q

liquefactive microscopic:

lack of nuclei surrounded by PMNs
little cellular debris
lots of eosinophilia

A

….

36
Q

caseous necrosis… gross appearance?

classic ex?

A

dead tissue appears as white, soft, cheesy-looking material (“caseous”)

ex. tuberculosis

37
Q

how is Tb transmitted?

what is the host response?

problem?

A

inhaled

phagocytksed by alveolar macrophages

Tb evades killing so the solution is to contain the infection in a GRANULOMA.

38
Q

What does a granuloma look like at the microscopic level?

A

central core: Tb infected macrphages

periphery:
Foamy macrophages (accum lipid)
Epithelioid macrophages (look like epi cells – really angry)
Giant cells (fused macrophages)
Lymphocytes
39
Q

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

epitheliod macrophages are activated

A

…

40
Q

progressive central necrosis in granulomas is bad because…

A

signals waning containment

41
Q

What is fat necrosis?

A

Focal destruction of fat

Not considered a specific pattern of necrosis

42
Q

What is fat necrosis characteristic of?

A

acute pancreatitis!

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

43
Q

What is the gross appearance of fat necrosis?

A

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

44
Q

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

A

..

45
Q

What is gangrenous necrosis?

A

widely used term clinically

not considered a distinct form of necrosis..

can be dry or wet

46
Q

what is dry gangrene?

A

ischemia, usually of distal limb

damage is COAGULATIVE NECROSIS!!

47
Q

what is wet gangrene?

A

dry gangrene superimposed bacterial infection: LIQUEFACTIVE NECROSIS

48
Q

what is gas gangrene?

A

Deadly form of wet gangrene associated with crepitus (ability to hear gas under skin)

Anaerobic bacteria that produce potent toxins (claustridium perfringes, etc)

49
Q

Apoptosis = programmed cell death..

it is a physiological response to?

A

sub-lethal damage

external signals

50
Q

What are the two pathways for apoptosis?

A

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

51
Q

Apoptosis - goes int o blebs - apoptotic bodies

expose phosphatidylserine on surface!! - recognized by phagocytic cells and eaten

A

…

52
Q

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

A

..

53
Q

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

A

…

54
Q

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!!

A

…

55
Q

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

A

…

56
Q

Microscopically… look at apoptotic cells!

A

…

57
Q

What is the clinical importance of apoptosis in neurodegenerative disease?

A

Protein misfolding disorders overwhelm mechanisms of proteostasis
(Alzheimer’s, Huntington’s, Parkinson’s)

Apoptosis contributes to degeneration

UPR is one mediator

58
Q

What is the clinical importance of apoptosis in infectious disease?

A

Infection by intracellular pathogens

Apoptosis kills the cell

59
Q

What is the clinical importance of apoptosis in carcinogenesis?

A

Normal cells: genotoxic damage activates p53
(Tumor suppressor role: if repair fails - apoptosis)

Cancer cells: p53 is abnormal
Damaged cells fail to die

60
Q

What is the clinical importance of apoptosis in cancer therapy?

A

Apoptosis induction: radiation, chemotherapy, hormone ablation therapy

61
Q

Many new drug targets for pro and anti apoptotic pathways

A

…

62
Q

Summary of necrosis…

A

Injury exceeds repair
Mostly pathologic

Death - energy failure

Morphology:
Cells swell
Membranes leak

Inflammatory response:
Strong

63
Q

Summary of apoptosis?

A

Programmed death
Physiologic or pathologic

Death: caspase activity

Morphology
Cells fragment - apoptotic bodies
Membranes remain intact

Inflammatory response:
Minimal

64
Q

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

A

…

65
Q

Hypoxia summary?

A

Inadequate O2
(Anemia or Displacement of O2 from erythrocytes)

May or may not be associated with ischemia

66
Q

Ischemia summary?

A

Restricted blood flow:

  • Hypoxia
  • Impaired delivery & removal of metabolites
  • Injury is more potent than hypoxia alone
67
Q

What triggers atheroschlerosis/ ischemic heart disease?

A

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)
68
Q

what is an atheroma?

A

accumulation of plaque

69
Q

dystrophic calcification stiffens the plaque (becomes fragile)

plaque ruptures.. platelets activated, thrombus forms, ischemic injury to downstream tissue!!

A

..

70
Q

What is the mechanism of ischemia-reperfusion injury?

A

Increased ROS generation (sudden influx of O2 to hypoxic tissue and sudden influx of inflamm cells)

complement binds to ischemic tissues!!

71
Q

outcome of ischemic injury?

A

Early injury - reversible

Sustained injury – irreversible:

  • Coagulative necrosis of ischemic tissues
  • Apoptosis of surviving, but damaged cells

Cellular Week 4 (11 decks)

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