09.25 Cell Injury and Death Flashcards
Common mechanisms of cell injury
deprivation
attack
radiation
free radicals
chemicals
types of cellular damage
enzymes: interrupts, disrrupts or otherwise alters enzyme function
membrane: plasma, nuclear or organelle membrane damaged
DNA: genetic mutation
water ionization by radiation
lipid peroxidation
hydroxyl free radical (OH-) can damage DNA and membrane phospholipids.
LH + OH- > L- + H2O
L- + O2 > LOO-
LOO- > LOOH + L- (repeat)
creating reactive oxygen species (ROS)
O2 + e > O2-
O2- + O2- +2H >SOD> H2O2 + O2
H2O2 + H2O2 > O2 + 2H2O OR OH-
from oxygen to ROS and defenses
cellular defense against free radicals
vit.E,C and A are all over the cell
superoxide dismutase (SOD) associates with copper or zinc to convert superoixde (O2-) into O2 and H2O2
water swelling of cells
- cause
- normal function
- abnormal function
- consequences
caused by hypoxia
- normal: with adequate O2, cell can make enough ATP. Na and Ca are passively leaked out of cell. require ATP to take it back in. ATPase is Na and Ca pump.
- abnormal: not enough O2 leads to anerobic respiration >>>not enough ATP + lactic acid >>> ion concentration, water and pH affected.
- consequences: organelle dysfunction, water and fat accumulation, clumping of chromatin, edema.
lipid accumulation
- normal
- diseased
- normal: non-esterified fatty acids and chylomicrons from adipose and food are absorbed by liver >> acetyl CoA turn them into triglycerides >> triglyceride taken by lipid acceptor and phospholipids and packaged by Golgi then released.
- diseased: not enough lipid acceptor, too much fat >> fat is stuck in liver, accumulate in liver, heart and kidney.
- caused by poor diet, diabetes, alcoholic hepatitis, etc.
stress adaptation
- thru growth
- hypertrohpy: larger cells
- hyperplasia: more cells
- cyclin-dependent kinases and CDK-inhibitors
- CDK>CDKI: divide
- CDK<cdki>
<li>
CDK: Cyc D, E, A</li>
<li>
CDKI: INKs, p21Cip1, p27Kip1</li>
</cdki>
stress adaptaion:
- other types of change in cell
- atrophy: autophagy
- autophagosomes wrapped up by Golgi and sER then digested. residual body excreted or stay.
- Lipofucin pigments result from, and is a marker of autophagy. brownish color
- metaplasia: changing cell types
- dysplasia: delay in cell maturation and differentiation
- storage: storing various compounds
necrosis: causes and effect
- when cell injury is irreversible
- when cell necrosis, it releases intracellular materials to env’t and irritate nearby cells.
- karyolysis: disintegration of nuclear membrane
- myelin body (structure with concentric layers) maybe observed
sequelae of necrosis, intracellular accumulation and pigments
- dystrophic (metastatic) calcification: black outlines on images
- intracellular may be a cause or consequence of cell injury and death.
- hemosiderin (yellowish but contain iron: turn blue for iron rxn)
- not to be confused with melanin
apoptosis overview
- definition, reason, process
- genetically encoded cell death program
- defense against dysregulated growth (cancer)
- involved in cell turnover and embryogenesis
- does not irritate nearby cells (no inflammation)
- cel shrinks away >> plasma membrane blebbing, cytoplasmic and nuclear condensation >> margination of condensed chromatin (crescent shape) >> nuclear and cellular fragmentation >> apoptotic bodies >> phagocytosis
- requires ATP
- if dysregulated, can lead to premature death or not enough death
DNA laddering
- the cellular DNA is fragmented: laddering shown in gel-separation
- necrotic cell DNA do not ladder.
apoptosis process
initiation
- cell death signal from drugs, radiation, ROS, etc.
commitment
- apoptosis inhibitor: Bcl-2, Bcl-X
- apoptosis promoter: Bax, Bak
- ultimately if caspses are activated, apoptosis proceeds
execution
apoptosis factor: extrinsic
- tumor necrosis factor (TNF) and TNF receptors on the plasma membrane
- TNF receptor-1s are spread out on plasma membrane >>when TNF binds, three receptors come t/g to form a structure >> intracellular part of 3-TNF receptor structure interact with TRADD to start the cascade. (caspase 8 is the intracellular mediateor between TNF and intrinsic factors)
apoptosis factor: intrinsic
- when stimulated, mitochondria release cytochrome c (can be inhibited by Bcl-2)
- cytochrome c (Apaf-2) and dAPT cometogether to associate with Apaf-1
- Apaf-1 structurally changes and interact with caspase-9 precursor (Apaf-3) which also structurally change to be activated.
- activated caspase-9 activates caspase-3 precursor
- activated caspase-3 is the executioner
apoptosis factor: other
- Bax and Bak allow mitochondria to leak proteins
- Bcl-2, Bcl-x and Mcl-1 control mitochondrial permeability to prevent leakage
- BH3-only proteins (Bim, Bid and Bad) bind to and thus block Bcl-2 and Bcl-x. they are also sensors of ER stress by misfolded proteins or DNA damage.
- Smac/DIABLO can inhibit IAP which can inhibit assembly and function of Apafs (apoptosome) and the caspase 3.
- Loss of contact with ECM or basement membrane cuts off survival signals and may initiate apoptosis
caspase activation
- can be promoted by [death ligand-death ligand receptor] and inhibited by [erythroprotein-erythroprotein receptor] complex.
- caspase activation cleaves GATA-1
- GATA-1 promotes Bcl-X and other stuff that promote survival and maturation
- cleaved GATA-1 leads to death caspase.
