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Integrative Phys > Reperfusion Injury > Flashcards

Reperfusion Injury Flashcards

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?

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?

A

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

25
Q

How can hydrogen peroxide form into hydroxyl?

A

Via the “Fenton reaction”

26
Q

What is the Fenton reaction?

A

When hydrogen peroxide reacts with Iron II to produce Iron III and the hydroxyl radical

27
Q

What is the most reactive free radical?

A

Hydroxyl

28
Q

What effects can the hydroxyl radical have on cells? (4)

A
  1. Lipid peroxidation
  2. Protein oxidation
  3. DNA damage
  4. Cytoskeletal damage
    * *all resulting in cell death
29
Q

How do hydroxyl radicals damage DNA?

A
  • Will convert guanine to 8-oxoG

- 8-oxoG will not bind to cytosine (like guanine would) and instead binds to adenine

30
Q

What are the three major components of the inflammatory reaction of reperfusion injury?

A
  1. Eicosanoids
  2. Cytokines
  3. Neutrophils
31
Q

How do eicosanoids form and play a role in lipid peroxidation of cell membranes?

A
  • 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
Q

What are the three types of eicosanoids?

A
  1. Prostaglandins
  2. Thromboxane
  3. Leukotrienes
33
Q

What are prostaglandins?

A
  • a protective vasodilatory effect in IRI
34
Q

What is the “life-span” of prostaglandins and what happens when it id depleted?

A
  • It is short-lived

- After depletion, vasoconstriction is left uninhibited, causing reduced local blood flow and exacerbation of ischemia

35
Q

What does plasma thromboxane promote?

A

Vasoconstriction and platelet aggregation

36
Q

How do leukotrienes cause inflammation (hint: directly and indirectly)?

A
  • Directly: at endothelial and smooth muscle cells

Indirectly: via neutrophils

37
Q

How do leukotrienes modify the endothelial cytoskeleton?

A
  • Increase vascular permeability

- Increase smooth muscle contraction (vasoconstriction)

38
Q

How to cytokines cause inflammation?

A
  • TNF-alpha (IL-1, IL-6, IL-8, platelet activating factor)
39
Q

What system do cytokines activate?

A

The complement system

40
Q

How is the complement system affected by reperfusion?

A
  • there is a depletion of complement protein factor B

- complement system will take alternative pathway

41
Q

What is the end product of the complement system?

A

Osmotic lysis

42
Q

How to neutrophils contribute to IRI? (2)

A
  • Physical obstruction of microvasculature

- Secretion of products that damage microvasculature

43
Q

Activated neutrophils are a major source of…?

A

ROS

44
Q

How are activated neutrophils generated?

A

Through NOX

45
Q

What do activated neutrophils secrete and how does it affect the membrane?

A
  • Secrete proteases like MMPs

- This causes the degradation of the endothelial basement membrane and extracellular matrix

46
Q

How do MMPs and TIMPs work together to maintain the extracellular matrix?

A
  • MMPs will degrade components of the ECM while TIMPs will inhibit MMPs
47
Q

What can happen in cerebral IRI due to elevation of MMPs? (4)

A
  • opening of the BBB
  • degradation of the basal lamina
  • increased capillary permeability
  • cerebral edema
48
Q

What are other changes that can occur due to IRI? (2)

A
  • Nitric oxide (NO)

- Endothelins

49
Q

TRUE/FALSE: Nitric oxide has concentration-dependent toxic effects on tissues and organs.

A

TRUE

50
Q

What happens to nitric oxide in the first 15 minutes of ischemia?

A
  • there is a surge of NO due to transient eNOS activation
51
Q

What happens to nitric oxide in early reperfusion?

A
  • 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
Q

What is necessary for maintenance of vascular tone?

A
  • eNOS-derived NO
53
Q

What happens when NO forms with a superoxide?

A
  • It forms peroxynitrite radical (ONOO-)

- This causes lipid peroxidation and membrane disruption

54
Q

What do the negative effects of NO depend on?

A
  • the duration of ischemia, magnitude of the injury, and the specific ischemic organ
55
Q

What do endothelins promote? What is this mediated by?

A
  • Vasoconstriction

- mediated by calcium

56
Q

What is the affect of ischemia on Endothelin-1? What does this cause?

A
  • Endothelin-1 will elevate

- This results in capillary vasoconstriction, neutrophil aggregation, and neutrophil-endothelial interactions

Integrative Phys (5 decks)

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