1-Cell Injury and Death Flashcards
cell survival
depends on
- maintain ability to produce energy/ATP
- adapt to adverse environmental conditions
injury when stressed beyond adaptation
cell response depends on
dose
duration
type of injury
pathway of cell injury
- healthy cell
- stress
- adaptation
- cell injury if inability to adapt
- severe progression
- irreversible injury
- necrosis or apoptosis
causes of cell injury
- lack oxygen/hypoxia
- physical agents/ trauma
- chemical agents and drugs
- infectious agents
- immunologic rxns
- genetic defects
- nutritional imbalances
damaged cellular functions
- aerobic respiration mitochondrial oxidative phosphorylation and ATP
- integrity of cell membranes
- proteins synthesis
- cytoskeleton
- genetic apparatus
injurious stimulus
- membrane damage
- protein/cytoskeletal damage
- DNA damage
MPD
mitochondrial damage
results
-dec ATP
-inc ROS = damage to lipids, proteins, DNA
entry/influx calcium
mechanism
- inc mitochondrial permeability
- binds to activate enzymes
-phospholipase breaks down phospholipids = membrane damage
-protease disrupt membrane/cytoskeletal proteins = membrane damage
-endonuclease breaks down DNA = nuclear damage
-ATPase break down ATP = dec ATP
membrane damage
mechanism
-plasma membrane = loss cellular components
-lysosomal membrane = enzymes digest cellular components
protein misfolding
mechanism
activates pro-apoptotic proteins
ER stress
5 major mechanisms
- influx of calcium into cells, lose calcium homeostasis
- mitochondrial damage
- depletion of ATP
- acc of oxygen free radicals
- defects in membrane permeability
sources of calcium
- extracellular
- mitochondria
- SER
causes of mitochondrial injury
- inc Ca in cytosol
- oxidative stress
- breakdown of phospholipids by phospholipase A2 and sphingomyelin into free FA and ceramides
mitochondrial necrosis pathway
- dec oxygen, toxins, radiation
- mito damage
- dec ATP + inc ROS
- cellular abnormalities
- necrosis
mitochondrial apoptosis pathway
- survival signals DNA, protein damage
- inc pro-apoptotic proteins + dec anti-apop
- leakage of proteins
- apoptosis
consequences of dec ATP
mitochondrial
- dec Na/K pump and Ca pump > influx of Ca, H2O, and Na, efflux of K = swelling + blebs
- inc anaerobic glycolysis > inc lactic acid > dec pH > clump nuclear chromatin
- detachment of ribosomes = dec protein synthesis
ROS
O2-, OH, ONOO, lipid peroxidase radicals > membrane damage = cell injury
lipid peroxidation
membranes
- unsat FA with double bonds attacked by radicals
- peroxidases formed
- unstable peroxidase react with membrane lipids to make more peroxidases
- self sustaining and great damaged until captured by vitamin E, C, A, beta carotene
protein oxidation
- side chains oxidized so change function/structure
- formation of disulfide bonds = cross linking
- cross links interupt folding
DNA damage with radicals
radicals interact with thymine = single stranded breaks in DNA = mutations (also shown in carcinogenesis)
removal of free radicals
- SOD (superoxide dismutase) converts superoxide to hydrogen peroxide
- glutathione peroxidase converts hydroxyl radical to hydrogen peroxide
- catalase converts hydrogen peroxide to water and oxygen
neutrophils
-do not divide
-multinucleated
-uses ROS to destroy bacteria
-1st line of defense
-can acc with cytokines and cell adhesion molecules
membrane permeability damage
found in most forms of cell injury
damage = activation of phospholipase in cytosol
no ATP prevents reacylation of phospholipids and dec synthesis so no repair
characteristics of necrotic cells
- swelling of ER and loss ribosomes
- lysosome rupture
- myelin figures
- nuclear condensation/pyknosis > fragmentation
- swollen mitochondria
- eosinophilic and glassy cytoplasm
necrosis is always pathologic
necrosis
definition
cell death from exogenous or endogenous damage leading to leaking cellular contents
not controlled so does not require signals
apoptosis
definition
programmed cell death from external or internal damage, physiologic, or develop
cell fragmentation and phagocytosis
to eliminate unwanted or irreparably damaged cells thru enzymatic degradation so not trigger inflamm
physiologic or pathologic
nuclear changes
necrosis
pkynosis-condensation
karyorrhexis- break up/fragmentation
karyolysis- dissolved
types of necrosis
- coagulative
- liquefactive
- caseous
- enzymatic fat
- fibrinoid
- gangrenous
coagulative necrosis
due to ischemia, hypoxia, reperfusion in organs with significant CT frameworks (except brain)
basic outline of cell preserved but no nuclei
liquefactive necrosis
usually brain tissue bc only glial cells and not CT
in abscess with pus (enzymatic digested neutrophils)
amorphous, granular, loss of cell and tissue structure
caseous necrosis
acc of mononuclear/macrophage that mediate chronic inflamm response and granuloma formation
grayish, whitish, yellowish, soft, friable, cheesy appearance
enzymatic fat necrosis
fatty acids react with calcium to form soap like substance
white, chalky appearance in fat cells or basophilic calcium
usually pancreatitis
fibrinoid necrosis
injury in blood vessels with acc of plasma proteins (fibrin and debris)
very eosinophilic
gangrenous necrosis
loss of circulation to a limb or bowel
wet gangrene = combo with superimposed bacterial infection
reperfusion
blood flow/oxygen restored to ischemic tissues but leads to large amounts of ROS
clot treatment for heart attack and stroke
necrosis serum tests
creatine kinase or troponin levels elevated in serum after MI = necrosis
physiological roles apoptosis
- embryogenesis
- hormone dependent involution
- cell celetion in proliferating cell pop
- normal immune defense vs viral infections or neoplastic cells aka cytotoxic T cell clearance
- removal self reactive lymphocyte clones
- removal cells served purpose i.e inflamm cells
pathologic conditions apoptosis
- cell death in tumors
- DNA damage from low doses of agents that would cause necrosis in high doses
- transplant rejection
- atrophy after duct obstruction
- some viral diseases
stages of apoptosis
- intrinsic activated (cytochrome c released) or extrinsic (receptor activated)
- initiation: intracell signals commit cell to apop by syn/activating initiator caspases
- execution: execution caspases catabolize cytoskeleton, activate endonucleases for DNA break down
- removal: removal round dead fragments of cells by macrophages
intrinsic apoptosis triggers
- growth factor withdrawal
- DNA damage via radiation, toxins, free radicals, p53 will act proapoptic Bcl-2 to stim Bax/Bak
- protein misfolding i.e ER stress
cyt c will release thru Bak/Bax dimerized channel in mito membrane
mitochondrial
extrinsic apoptosis triggers
- receptor ligand interactions aka Fas or TNF (tumor necrosis factor) receptor > act adaptor proteins to bind caspases
chemicals for cell injury
- acetaminophen: highly reactive quinone reacts with protein, DNA = oxidative stress
- carbon tetrachloride: metabolite reacts w/ membrane and ER
- heavy metals/cyanide: mitochondria
- phalloidin/paclitaxel: cytoskeleton
- chemotherapeutic alkylating agents: DNA
SER induction
aka hypertrophy
adaptive response to become more efficient if metabolizing or detoxing barbituates + p-450 mixed function oxidase system
