Cell injury/death Flashcards
What are some causes of cell injury?
Ischemia Physical agents Chemical agents Infectious agents Immune reactions Genetic abnormalities Nutritional imbalances Aging
Where are sites within the cell that vulnerable/lead to injury?
Mitochondria Membranes Ribosomes Cytoskeleton Genome
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
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)
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!!
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)
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
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
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
Why does oxidative stress occur?
imbalance between ROS and ROS scavenging systems
**ROS = superoxide 02-, hydrogen peroxide (h2o2), hydroxyl radical (Oh-)
What are some examples ROS scavengers?
Vitamens C and E (antioxidant activity)
Enzymes: superoxide dismutase, catalase, glutathione peroxidase
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
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!!
If there is no stress in the cell… p53 transcription factor is…
unstable due to ubiquitination (targeted to proteasome)
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
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
…
P53 – engineered to kill cell if it cannot repair the DNA damage!
…
Necrosis is mostly…
pathologic!
- damage to a cell exceeds repair capacity
- viral infection, toxins, ischemic injury
what are some exs of physiologic necrosis?
ischemia of uterine lining during menstruation
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
pyknosis
shrinkage
karyorrhexis
fragmentation
karyolysis
dissolution/dissolve of membrane
necrotic cells trigger inflammation
…
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
