09.25 Cell Injury and Death

Question 1

Common mechanisms of cell injury

Answer 1

deprivation

attack

radiation

free radicals

chemicals

Question 2

types of cellular damage

Answer 2

enzymes: interrupts, disrrupts or otherwise alters enzyme function
membrane: plasma, nuclear or organelle membrane damaged

DNA: genetic mutation

Question 3

water ionization by radiation

Answer 3

Question 4

lipid peroxidation

Answer 4

hydroxyl free radical (OH-) can damage DNA and membrane phospholipids.

LH + OH- > L- + H2O

L- + O2 > LOO-

LOO- > LOOH + L- (repeat)

Question 5

creating reactive oxygen species (ROS)

Answer 5

O2 + e > O2-

O2- + O2- +2H >SOD> H2O2 + O2

H2O2 + H2O2 > O2 + 2H2O OR OH-

Question 6

from oxygen to ROS and defenses

Answer 6

Question 7

cellular defense against free radicals

Answer 7

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

Question 8

water swelling of cells

• cause
• normal function
• abnormal function
• consequences

Answer 8

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.

Question 9

lipid accumulation

• normal
• diseased

Answer 9

• 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.

Question 10

stress adaptation

• thru growth

Answer 10

• 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>

Question 11

stress adaptaion:

• other types of change in cell

Answer 11

• 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

Question 12

necrosis: causes and effect

Answer 12

• 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

Question 13

Answer 13

Question 14

sequelae of necrosis, intracellular accumulation and pigments

Answer 14

• 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

Question 15

apoptosis overview

• definition, reason, process

Answer 15

• 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

Question 16

DNA laddering

Answer 16

• the cellular DNA is fragmented: laddering shown in gel-separation
• necrotic cell DNA do not ladder.

Question 17

apoptosis process

Answer 17

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

Question 18

apoptosis factor: extrinsic

Answer 18

• 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)

Question 19

apoptosis factor: intrinsic

Answer 19

• 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

Question 20

apoptosis factor: other

Answer 20

• 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

Question 21

caspase activation

Answer 21

• 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.

Question 22

Answer 22