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Reperfusion Injury Flashcards

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1
Q

What are the activated genes during ischemia?

A

Cytokines and mediators or inflammation + immune cell infiltration

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2
Q

What are the repressed genes during ischemia?

A
  • Energy production
  • Mitochondrial respiration
  • Fatty acid oxidation
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3
Q

What are the three mechanisms of reperfusion injury?

A
  • Calcium overload
  • Generation of ROS
  • Inflammation
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4
Q

What is MPTP and where is it located?

A
  • a nonselective pore that sits on the inner core of the mitochondria
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5
Q

What is MPTP triggered by to become permeable?

A
  • High pH levels
  • Calcium overload
  • Burst of ROS (oxidative stress)
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6
Q

What happens to the ETC during prolonged opening of MPTP?

A

Will become inhibited which will in turn increase ROS and keep MPTP open

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7
Q

What are other irreversible alterations caused by prolonged opening of MPTP? (4)

A
  • Collapse of mitochondrial membrane potential
  • ATP and NAD depletion
  • Release of the accumulated calcium
  • Swelling of matrix causing rupture and release of important enzymes
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8
Q

What can the prolonged opening of MPTP lead to?

A

Apoptosis

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9
Q

What is ROS?

A

Reactive oxygen species

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10
Q

What are the enzymatic source of oxidative stress? (3)

A
  1. Xanthine Oxidase (XO)
  2. NADPH oxidase (NOX)
  3. Uncoupled NO synthase (NOS)
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11
Q

Where are XO and NOX typically found?

A

Intestines, lungs, heart, brain, muscle, liver, pancreas, stomach, and kidney

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12
Q

Where are NOS typically found?

A

Liver, heart, and aortic endothelial cells

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13
Q

What are the major ROS involved in IRI?

A
  • Superoxide anion (O2-)
  • Hydrogen peroxide (H2O2)
  • Hydroxyl radial
  • Nitric Oxide
  • Peroxynitrite (ONOO-)
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14
Q

How are can superoxides be generated in the mitochondria?

A

Formed from electrons leaking from complexes I and III in the mitochondria

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15
Q

What converts XD into the enzyme xanthine oxidase (XO)?

A

A calcium dependent proteolytic enzyme that is activated during ischemia

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16
Q

How does XO cause the generation of superoxide?

A

Superoxides are a byproduct of XO catalyzing hypoxanthine into xanthine and the latter into uric acid

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17
Q

What is NOX activated by?

A

Oxygen that is introduced via reperfusion of cells

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18
Q

How does NOX cause the generation of superoxide?

A

Superoxides are a byproduct of NOX breaking down NADPH into NADP+ and H+

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19
Q

What does NOS produce?

A

Nitric oxide (NO)

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20
Q

What are the three types of NOS?

A
  1. Endothelial NOS (eNOS)
  2. Neuronal NOS (nNOS)
  3. Inducible NOS (iNOS)
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21
Q

What is eNOS dependent on?

A

Calcium

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22
Q

What is the importance of BH4 in conjunction with eNOS?

A

In a coupled state, eNOS is activated by BH4 to produce mainly NO a little superoxide
- ETC can run smoothly

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23
Q

What happens with eNOS under oxidative stress?

Study These Flashcards
A
  • BH4 is broken down, causing uncoupled eNOS to produce less NO and more superoxide
24
Q

How does hydrogen peroxide form from superoxide radical?

Study These Flashcards
A

Via enzyme SOD which converts superoxide into hydrogen peroxide and oxygen (less harmful)

25
How can hydrogen peroxide form into hydroxyl?
Via the "Fenton reaction"
26
What is the Fenton reaction?
When hydrogen peroxide reacts with Iron II to produce Iron III and the hydroxyl radical
27
What is the most reactive free radical?
Hydroxyl
28
What effects can the hydroxyl radical have on cells? (4)
1. Lipid peroxidation 2. Protein oxidation 3. DNA damage 4. Cytoskeletal damage * *all resulting in cell death
29
How do hydroxyl radicals damage DNA?
- Will convert guanine to 8-oxoG | - 8-oxoG will not bind to cytosine (like guanine would) and instead binds to adenine
30
What are the three major components of the inflammatory reaction of reperfusion injury?
1. Eicosanoids 2. Cytokines 3. Neutrophils
31
How do eicosanoids form and play a role in lipid peroxidation of cell membranes?
- Breakdown of phospholipids produces arachidonic acid - arachidonic acid is the main substrate for production of eicosanoids - eicosanoids will disrupt cell permeability and cause cell death
32
What are the three types of eicosanoids?
1. Prostaglandins 2. Thromboxane 3. Leukotrienes
33
What are prostaglandins?
- a protective vasodilatory effect in IRI
34
What is the "life-span" of prostaglandins and what happens when it id depleted?
- It is short-lived | - After depletion, vasoconstriction is left uninhibited, causing reduced local blood flow and exacerbation of ischemia
35
What does plasma thromboxane promote?
Vasoconstriction and platelet aggregation
36
How do leukotrienes cause inflammation (hint: directly and indirectly)?
- Directly: at endothelial and smooth muscle cells | Indirectly: via neutrophils
37
How do leukotrienes modify the endothelial cytoskeleton?
- Increase vascular permeability | - Increase smooth muscle contraction (vasoconstriction)
38
How to cytokines cause inflammation?
- TNF-alpha (IL-1, IL-6, IL-8, platelet activating factor)
39
What system do cytokines activate?
The complement system
40
How is the complement system affected by reperfusion?
- there is a depletion of complement protein factor B | - complement system will take alternative pathway
41
What is the end product of the complement system?
Osmotic lysis
42
How to neutrophils contribute to IRI? (2)
- Physical obstruction of microvasculature | - Secretion of products that damage microvasculature
43
Activated neutrophils are a major source of...?
ROS
44
How are activated neutrophils generated?
Through NOX
45
What do activated neutrophils secrete and how does it affect the membrane?
- Secrete proteases like MMPs | - This causes the degradation of the endothelial basement membrane and extracellular matrix
46
How do MMPs and TIMPs work together to maintain the extracellular matrix?
- MMPs will degrade components of the ECM while TIMPs will inhibit MMPs
47
What can happen in cerebral IRI due to elevation of MMPs? (4)
- opening of the BBB - degradation of the basal lamina - increased capillary permeability - cerebral edema
48
What are other changes that can occur due to IRI? (2)
- Nitric oxide (NO) | - Endothelins
49
TRUE/FALSE: Nitric oxide has concentration-dependent toxic effects on tissues and organs.
TRUE
50
What happens to nitric oxide in the first 15 minutes of ischemia?
- there is a surge of NO due to transient eNOS activation
51
What happens to nitric oxide in early reperfusion?
- there is a loss of functional eNOS, causing a fall of NO and an increase in ROS production - causes a decline in endothelial function
52
What is necessary for maintenance of vascular tone?
- eNOS-derived NO
53
What happens when NO forms with a superoxide?
- It forms peroxynitrite radical (ONOO-) | - This causes lipid peroxidation and membrane disruption
54
What do the negative effects of NO depend on?
- the duration of ischemia, magnitude of the injury, and the specific ischemic organ
55
What do endothelins promote? What is this mediated by?
- Vasoconstriction | - mediated by calcium
56
What is the affect of ischemia on Endothelin-1? What does this cause?
- Endothelin-1 will elevate | - This results in capillary vasoconstriction, neutrophil aggregation, and neutrophil-endothelial interactions

Integrative Phys (5 decks)

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