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Block 1 lectures > Cell Injury (Drake) > Flashcards

Cell Injury (Drake) Flashcards

1
Q

B1W4Drake-Celltissue/injury-1

Apoptosis

A

Programmed cell death (physiological or pathological)

Single cells

Requires ATP

No loss of membrane integrity

Little release of cell contents (apart from extrusion-planned)

Little inflammation

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2
Q

B1W4Drake-Celltissue/injury-1

Causes of Necrosis

A

(1) ischemia
(2) mitochondrial poisoning
(3) membrane damage agents (ROS, bacterial enzymes)

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3
Q

B1W4Drake-Celltissue/injury-1

Sequence of events for cell death in ischemia

A

1) Decreased blood flow
2) Decreased oxygen
3) Decreased ATP
4) Decreased Na/K pump (increased cytoplasmic Na+ and Ca++)
5) Loss of mitochondrial electron transport function
6) Loss of inner mitochondrial membrane integrity
7) Lysosomes degrade cell constituents

PROCESS IS REVERSIBLE UNTIL LOSS OF INNER MITOCHONDRIAL MEMBRANE INTEGRITY

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4
Q

B1W4Drake-Celltissue/injury-1

Consequences of ischemia

A

Decreased oxidative phosphorylation –> decreased ATP –>

(1) ER swelling Cell swelling (decreased Na+ pump activity)
(2) clumping of nuclear chromatin
(3) decreased protein synthesis and increased lipid deposition

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5
Q

B1W4Drake-Celltissue/injury-1

Role of increased cytosolic Calcium in cell injury

A

activation of cellular enzymes–>

(1) membrane damage (due to phospholipases and proteases)
(2) nuclear damage (due to endonucleases)
(3) decreased ATP (due to ATPase activity)

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6
Q

B1W4Drake-Celltissue/injury-1

Clinical conditions leading to necrosis

A

Ischemia and hypoxia

Ischemia reperfusion injury

Inflammation and infections

Chemical injury

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7
Q

B1W4Drake-Celltissue/injury-1

Stages of apoptosis

A
  1. Signaling stage - Initiation (generate activated initiator caspase from procaspases)
  2. Effector stage - Death pathway engaged (caspase cascade generates effector caspases)
  3. Terminal stage - Cell death. Morphologic changes. (endonucleases digest DNA, cytoskeleton broken apart)
  4. Phagocytosis of apoptotic cell
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8
Q

Necrosis

A

Occurs in many adjacent cells

Passive response

Does not require ATP

Disruption of organalle fxn

Release of cell contents

Strong inflammatory rxn

Always pathological

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9
Q

What are all initiators of necrosis associated with?

A

Decreased ATP

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10
Q

How can you tell if a tissue is undergoing necrosis?

A

Released intracellular proteins enter the blood and are measured as markers of tissue damage (eg liver enzymes; cardiac enzymes and proteins).

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11
Q

Where does the intrinsic pathway of apoptosis occur?

A

Mitochondria

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12
Q

Molecules involved in intrinsic pathway of apoptosis

A

1) Bcl2 (regulator): sits on membrane of mitochondria and binds Bax/Bac to keep it from forming mitochondrial pores; is anti-apoptotic
2) Bax/Bac (effector): forms pore in mitochondrial outer membrane; is pro-apoptotic
3) BH3 (sensor): when cell wants to undergo apoptosis, BH3 binds to Bcl2, freeing Bax/Bac to form mitochondrial pores; is pro-apoptotic

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13
Q

After mitochondrial pore is formed in intrinisc pathway of apoptosis, what happens?

A

Cytochrome C and other proteins released into cytoplasm –> initiates formation of caspase complex called apoptosome –> caspase pathway that leads to apoptosis

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14
Q

Extrinsic pathway of apoptosis

A

Fas death receptor present on all cells binds Fas ligand on killer T cell –> aggregate –> adaptor protein FADD attracts procaspase (forming DISC complex) –> initiate effector caspase cascade –> apoptosis

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15
Q

Terminal stage of apoptosis

A

Executioner caspases: activate endonucleases (DNA fragmentation), degrade microfilaments (cytoplasmic blebbing), proteolyse lamin (nuclear blebbing)

Transglutaminase inside cell does protein cross-linking

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16
Q

Why doesn’t apoptosis result in inflammation?

A

No release of cytokines

Apoptotic cells are rapidly cleared

Plasma membrane is preserved

Apoptotic cells secrete inhibitors of inflammation

17
Q

Diseases that result from apoptosis (both decreased and increased apoptosis)?

A

Decreased: cancer, viral infection (herpes), autoimmune (lupus)

Increased: Alzheimers, Type I diabetes, organ atrophy, ischemia (myocardial infarction, stroke)

18
Q

Reactive Oxygen Species (ROS)

A

Molecules that can generate free radicals and/or are already free radicals

19
Q

How are cells exposed to ROS?

A

1) Normal oxidative phosphorylation
2) Activation of certain receptors
3) Chemicals from environment
4) Metabolites of drugs and environmental agents
5) Impaired function of defense enzymes/mechanisms

20
Q

ROS negative effects on proteins

A

1) Modification of SH groups (S-S crosslinking)
2) Adduct formation with lysine, tyrosine, cysteine
3) Protein unfolding
4) Protein scission (splitting apart)

21
Q

ROS negative effects on lipids

A

1) Changes in membrane fluidity (damage membrane)
2) Production of receptor ligands
3) Become antigenic
4) Lipid ROS propagates ROS formation (BAD! Due to double bonds of fatty acids)
5) Fatty acid oxidation
6) Scission of lipids (measure malondialdehyde to see if this is happening)
7) Cross-linking lipids

22
Q

ROS negative effects on DNA

A

1) Base mutations/changes (usually by adding hydroxyl radical; some lead to apoptosis)
2) Chromosome breaks

23
Q

Glutathione (GSH)

A

Very important antioxidant (a metabolite)

Turns H2O2 –> H2O (in general quenches oxygen free radicals)

HIGH ratio of reduced to oxidized glutathione (GSH:GSSG) tells you that there’s no cellular oxidative stress

24
Q

Glutathione peroxidase

A

Enzyme that catalyzes the reaction of Glutathione with H2O2 to turn it into H2O (also at the same time turns GSH to GSSG)

25
Q

Glutathione reductase

A

Enzyme that catalyzes the reaction where GSSG reduces NADPH to NADP+ (at the same time turns GSSG to GSH)

26
Q

Fixing lipid free radicals: Vitamin E (tocopherol) and Vitamin C (ascorbic acid)

A

Antioxidants (metabolites)

Vitamin E in plasma membrane finds lipid free radicals and gets rid of them but turns into a free radical itself!

Vitamin C in water soluble compartment picks up radical from vitamin E

Other enzymes get rid of Vitamin C’s free radical

27
Q

Enzymes to get superoxide to H2O

A

Superoxide dismutase (SOD): superoxide (O2) –> H2O2

Catalase: H2O2 –> H2O

28
Q

Heme oxygenase

A

Controls free iron in the process of heme catabolism

(Fe2+ can generate hydroxyl radical!)

29
Q

Fixing protein free radicals that create damaged or unfolded proteins

A

1) Chapreone synthesis: they help re-fold proteins
2) Ubiquitin: tag misfolded proteins and degrade
3) Unfolded protein response (UPR): turn on tx of genes to respond to ROS stress (glutathione, folding proteins, etc) and turn off translation of unnecessary proteins

30
Q

Fixing DNA free radicals that cause DNA damage

A

Just repair DNA as usual!

Ends in inhibition of cell cycle or apoptosis if damage is severe

31
Q

How do cells detect ROS via Nrf2?

A

Nrf2 is a TF that binds antioxidant response element (ARE) and increases expression of things to get rid of ROS (GSH, proteasome, anti-inflammatory)

Normally, Nrf2 constantly made and degraded

Nrf2 is normally bound to Keap1 (sensory molecule) which promotes degradation by ubiquitin

ROS prevents Keap1 from binding Nrf2 (ROS oxidizes thiols on Keap1) so Nrf2 increases

32
Q

How do cells detect hypoxia via HIF?

A

HIFa and HIFb complex is TF that initiates tx of genes to restore O2, energy homeostasis, OR initiate apoptosis

Normally, HIF constantly made and degraded

HIFa normally has PHD (sensory protein) add OH, which promotes degradation by ubiquitin

ROS inactivates PHD so it can no longer tag HIFa with OH for degradation, so HIF increases

Block 1 lectures (29 decks)

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