Cell/Tissue Injury Flashcards
Causes of cell injury
Hypoxia Ischemia (causes hypoxia) Physical agents Drugs and chemicals Infectious agents Immunological rxns Nutritional imbalances Genetic
Response of cells to injury
Adaptation
Injury
Death
Adaptation
Cell undergoes changes that allow it to deal with stress
Injury and 2 types
If cell is unable to adapt to stress
Reversible - if injurious agent removed then it reverts back to normal
Irreversible - Death is inevitable
Response of cell to injury depends on
Lenght of time
Dose
Type of cell
Example of type of cell adaption
Neuron less able to adapt than muscle cell
Ischemia and hypoxia causes
lack of oxygen which decreases ATP
Oxygen derived free radicals will cause
Degradation of cellular proteins, membrane phospholipids, and nucleic acids
Role of calcium in cell injury
If injury interferes with calcium ATPases, calcium will enter the cell and activate enzymes
Calcium activated enzymes and what they do…one other thing it does
Phospholipiases - destroy membrane phospholipids
Proteases - destroy proteins f membrane cytoskeleton
Endonucleases - DNA/chromatin fragmentation
ATPases - ATP depletion
Also causes mitochondrial permeability so no ATP can be generated
ATP depletion leads to what and caused by what?
Cause - decreased ATP synthesis or activation of ATPases
Effect - loss of integrity of cell membrane
Common themes in cell death
oxygen
calcium
ATP depletion
Defects in membrane permeability
Ischemic/hypoxic reversible injury
Decrease or loss of ATP within cell due to decrease in mitochondrial function…decrease in ATP causes increase in anaerobic glycolysis (generates lactic acid and lowers pH…leads to decreased activity and inactivation of intracellular enzymes…also causes failure of sodium pumps of cells membrane…influx of sodium and water causes swelling which impairs function)
Hypoxia/ischemic irreversible injruy
Inability to reverse mitochondrial effects
Profoud distrubance to cell membrane due to loss of phospholipids from membrane (because of decrease in production due to lack of ATP and increase in phospholipase activity),
cytoskeletal abnormalities (calcium activated proteases),
reperfusion injury (oxygen free radicals generated…can extend the injury),
lipid breakdown of products that result from phospholipid degradation have detergent effect on membrane,
loss of intracellular amino acids (mostly from glycine…these protect from oxidative damage)
Necrosis morphologic changes
Increased eosinophilia (cytoplasm stains deep pink when stained with H and E)…due to more avid binding of eosin to denatured proteins
Vacuolization (due to digestion of organelles)
Calcification
Nuclear necrotic changes
1 of 3
Karyolysis - stains pale blue (vs dark blue)…due to DNA degradation by DNA-ases
Pyknosis - Nuecleus shrinks and becomes darker blue…due to chromatin condensation
Karyorrhexis - nucleus undergoes fragmentation
After 2 days of onset, nucleus disappears
Morphology of necrotic tissue
Coagulative - outlines of each cell are preserved…occurs when denaturation of cellular proteins predominates…cell does not autolyze…from ischemia/hypoxia
Liquefactive - cells disappear due to digestion and lysis by enzymes that are derived from cells own lysosomes or white blood cells within area (focal bacterial)
Caseous - appears cheesy…fragmented cells and granular debri…tuberculosis
Intrinsic activaiton of initiator caspase
Certain stressors activate intracytoplasmic sensor proteins (member of Bcl-2 family (subclassed BH3- only)…sensors activate Bax and Bak which polymerize into oligomers, insert into mitochondrial membrane…create channel that allow proteins normally within inner mitochondrial membrane to leak into cytoplasm (Bax and Bak also inhibit anti-apoptotic proteins Bcl-x and Bcl-2)…because cytochrome c leaks out, will bind to Apaf-1 whcih forms apoptosome hexamer…apoptosome binds to and activates initator caspase 9 which activates caspase 9 molecules
Extrinsic pathway of apoptosis
Cell membranes have deathreceptors (like TNFR 1 and Fas)…ligand binds and activates capases 8 and 10…causes activation of other initiator caspases
Execution phase of apoptosis
Activated intiator caspase activate executioner caspases (3 and 6)…degrade critical components…cell death
Morphologic apoptosis effects
Minimal membrane damage…nuclear chromatin condenses and aggregates to membrane…blebs to form apoptotic bodies…no inflammatory response…involves small numbers of cells
Autophagy steps
Autophagic vacuole fuses with lysosome…enzymes digest organelles and move back into cytoplasm
This is good for nutritionally deprived cells
Genetic regulation of autophagy
Atg genes
Pathologic? # of cells Apoptotic bodies Inflammatory response Membrane damage
Apoptosis vs. necrosis
Necrosis - always, apop - sometimes Necrosis - many cells Bodies only in apop Apop has no inflam resp Minimal mem damage in apop
