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Principal cell death mechanisms include
- necrosis
- apoptosis
- and necroptosis, a combination of the two
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At point of injury, the level of homeostatis ability reversibly changes from normal steady level to altered steady levels. However, when the change is big enough it becomes irreversible, necrosis starts.
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Cell death by necrosis
Normal -> reversible swelling -> irreversible swelling w/ mitochondrial changes and chromatin pattern reserved -> desintegration w/ membrane breakdown, releasing cell contents which can lead to inflammatory responses
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karyolysis
- Cell nucleus in necrosis, lysis of nucleus
- there can be absence of nucleus when necrosis occurs
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necrosis
- Desintegration of nucleus - condensed chromatin; shriveled membrane
- Swollen mitochondria w/ deposits.
- Increased intracellular volumes
- Aggregated cytoskeletal elements
- Dilated vesicular ER
- Disaggregated ribosomes
- Myelin bodies (or “Figures”) - autophagolysomes filled with nondigestible lipid and protein material in necrotic cells.
- Swollen cell.
- Plasma membrane bleb or breakdown.
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Summary of time course of hypoxia leading to necrosis
- Less oxygen
- Less oxidative phosphorylation
- less ATP
- -> increased glycolysis -> decreased pH
- -> decreased Na-K pump activity (can be shown by ECG, EEG) -> influx Na+ and Ca2+ -> swelling ER -> disruption polysomes
- disruption cristae - loss function
- pyknosis (nucleus condenses) and karyorrhexis (nuclear rupture) - entry vital dye
- decreased pH & lysosomes lysis
- karyolysis - loss enzymes
- mito - matrix deposites and calcification
- inflammatory response
- myelin figures
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An example of an enzyme leaking into the blood from irreversibly injured cells is _______ in liver damage.
alanine aminotransferase
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Sequelae of necrosis
- Intracellular accumulations and pigments
- Dystrophic calcification (cf Metastatic calcification, eg due to excess of vit D, precipitating and damaging).
- Intracellular accumulations may be a consequences or causes of cell injury and death
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Tissue Patterns of Necrosis
- Coagulative necrosis - no striations (for muscle cells), no nuclei, some lymphocytes visible; heart, muscle, kidney
- Liquefactive necrosis - due to bacterial infection; happens in the oral cavity when the gum is involved, brain
- Suppurative necrosis - a type of Liquefactive necrosis; skin, oral cavity
- Caseous necrosis - in lung (tuberculosis), lymph node-granuloma, adrenal gland (w/ calcification)
- Fat necrosis - in pancreas when fat is split by pancreatic enzymes, omentum (w/ saponification)
- Fibrinoid necrosis - artery (constriction)
- Other
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Cardiac infarct
- coagulative necrosis-gross
- Cells that are dead remain, but stain more densely because they’re more permeable, can take up more hues
- some lymphocytes because necrosis irritates neighboring cells
- Striations in the normal muscle are gone
- Fatal if large, men in 50s higher risk; estrogen is protective
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Brain infarct
Liquefactive necrosis
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Suppurative necrosis
- skin, oral cavity
- Due to bacteria
- lymphocytes (WBCs) visible in the middle
- pus present
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_________ are often produced on reperfusion of ischemic tissues and cause cell injury.
Reactive oxygen species
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apoptosis
- A genetically encoded cell death program defined by characteristic morphologic and biochemical changes
- A cellular defense against dysregulated growth
- “Dropping off”, controlled cell deletion, complementary to mitosis. Defined by structural changes.
- PROGRAMMED CELL DEATH - initiated by specific signals, requires de novo gene expression
- PHYSIOLOGICAL CELL DEATH - initiated by physiological signals, involved in cell turnover and embryogenesis
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Condensation, fragmentation, phagocytosis and secondary necrosis
- Condensation - nuclear changes; mitochondria conserved
- fragmentation - membrane intact; doesn't cause inflammation, taken up by neighboring macrophage
- phagocytosis and secondary necrosis - digestion by macrophages and other cells
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Mechanisms of apoptosis
- two pathways - differ in induction and regulation, both activate caspases.
- Mitochondrial/intrinsic pathway - proteins of the BCL2 family (effectors: BAK, BAX; regulators: BCL2, BCL-XL), which regulate mitochondrial permeability, become imbalanced (induced by cell injurious signals such as GF withdrawl, DNA damage, protein misfolding) and leakage of various substances from mitochondria (CytC) leads to caspase activation.
- Death receptor/extrinsic pathway - signals from plasma membrane receptors -> assembly of adaptor proteins into a “death-including signaling complex” -> activates caspases
- Sometimes activate NF-kB pathway for survival
- Most cases caspases for apoptosis
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Activation of caspases leads to
- nuclear fragmentation and breakdown of cytoskeleton
- formation of cytoplasmic bleb -> apoptotic body -> phagocytosis
- Caspase 3 is one of the major executioner caspases
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Normal cell -> cell shrinkage away from neighboring cells -> plasma membrane blebbing, cytoplasmic and nuclear condensation -> margination of condensed chromatin (crest-like shape) -> nuclear and cellular fragmentation and apoptotic bodies -> phagocytosis
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Refractory anemia
genetic defect -> apoptosis in the bone marrow
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Run the gel
- Apoptosis -> ladder - nucleosomes
- Necrosis -> smear
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Released Cyt C from mitochondria
- activate Apaf-1
- convert caspase-9 from precursor form to active form
- activate caspase-3, the main executioner caspase
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_________ allow proteins to leak out of mitochondria; _________ control mitochondrial permeability and prevent leakage; ________ bind and block ________, thus acting as sensors of ER stress by misfolded proteins, or of DNA damage.
- Bax and Bak
- Bcl-2, Bcl-x, and Mcl-1
- BH3-only proteins, such as Bim, Bid and Bad,
- Bcl-2 and Bcl-x
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Molecular mechanism of TNF-mediated necroptosis
- Crosslinking of TNFR1 by TNF causes recruitment of RIP1 and RIP3 along with caspase 8.
- Activation of the caspase leads to apoptosis. Inhibition of caspase 8, as may occur in some viral infections,allows RIP1 and RIP3 to initiate signals that affect mitochondrial generation of ATP and ROS. This is followed by events typical of necrosis.
- The key difference is that there’s the same signal from the outside, but the cell situation is different
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Role of mitochondria in cell injury and death. Mitochondria are affected by a variety of injurious stimuli and their abnormalities lead to necrosis or apoptosis.
- O2 decrease, ... -> ATP decrease/ROS increase -> cellular abnormalities -> necrosis
- death signals, ... -> leakage -> apoptosis
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Morphological contrast
- NECROSIS
- - Karyolysis and pyknosis
- - Cell swelling
- - Organelles damaged
- - Disintegration
- APOPTOSIS
- - Karyorrhexis and pyknosis
- - Cell shrinkage
- - Organelles at first intact
- - Apoptotic bodies
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Biochemical contrast
- NECROSIS
- - Increased cellular Na+ and Ca++
- - Loss of K+ ions
- - Loss of glycogen
- APOPTOSIS
- - DNA ladders
- - Evidence of caspase activation
- - P-Serine Flip- Annexin V
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Physiological
- NECROSIS
- - Hypoxia
- - Lytic viral infections
- - Complement attack
- - Hyperthermia
- APOPTOSIS
- - Embryogenesis
- - Organ involution
- - Immune cytotoxicity
- - Withdrawal of growth factors
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Potential mechanisms
- NECROSIS
- - Cell membrane damage
- - Depletion of ATP
- APOPTOSIS
- - Activation of proteases
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List and explain different types of necrosis
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