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Boards: Shock/Ischemia/CPR > Ischemia-Reperfusion Injury - SACCM 8, SAER 158 > Flashcards

Ischemia-Reperfusion Injury - SACCM 8, SAER 158 Flashcards

1
Q

Define free radicals

A

reactive atoms with one or more unpaired electrons

technically O2 has 2 free unpaired electrons in the outer shell - but not highly reactive becasue the unpaired electrons orbit in parallel around the oxygen atom

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2
Q

Describe the stages of oxygen reduction in health

A

95% in health reduced to water H2O
* O2 –> reduced to superoxide anion (O-2)
* superoxide dismutase (SOD) –> H2O2 (hydrogen peroxide) –> catalase/glutathione peroxidase –> 2 x H2O + O2

5% –> will undergo only partial reduction and cause odixative injuries

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3
Q

What is the name of the most cytotoxic reaction of the oxidative pathways?

A

Fenton/Haber-Weiss reaction

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4
Q

Describe the Fenton/Haber-Weiss reaction

A

Name explanation
* Fenton describes the reduction of Ferrous (Fe32) ion back to Ferric (Fe3+) ion
* Haber-Weiss describes the whole process/net summary

Picture => see bottom is just the summary of the 2 equations on top

Ferric ion + superoxide ion –> Ferrous ion + + O2

Ferrous ion + hydrogen peroxide –> ferric ion + hydroxyl free radial + hydroxyl anion

net summary
superoxide + hydrogen peroxide –> O2 + hydroxy free radical + hydroxyl anion

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5
Q

Describe the myoloperoxidase reaction

A

Occurs in phagocytic vesicles of neutrophils - important for killing bacteria

H2O2 reacting with chloride –> hypochlorous acid (ROS)

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6
Q

Describe three functions of nitric oxide (NO) in health

A

vasodilator
platelet inhibitor
cell messanger

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7
Q

What is the most common reactive nitrogen species and how is it produced?

A

peroxynitrite (ONO-2)

NO + O2- (superoxide) –> ONO2-

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8
Q

Describe the steps happening during the ischemic phase of ischemia-reperfusion injury

A
  • anaerobic metabolism –> H+ ion accumulation –> intracellular acidosis –> enzyme dysfunction + damage to regulatory membrane channel proteins
  • ATP depletion –> dysfunction of ATP-dependent ion pumps –> influx of Na+, Ca++, Cl- and efflux of K+
  • IC Na accumulation –> water influx –> cellular swelling
  • cytoplasmic Ca++ accumulation –> faciliates ROS formation, initiates apoptosis and necrosis
  • ATP degradation to adenosine –> inosine –> hypoxanthine
  • Ca++ –> activates calpain –> converts xanthine dehydrogenase to xanthine oxidase
  • xanthine oxidase requires O2, so xanthine oxidase and hypoxanthine accumulate
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9
Q

Describe the steps during the reperfusion phase of ischemia reperfusion injury

A
  • xanthine oxidase and hypoxanthine accumulated –> O2 now available –> oxidases hypoxanthine to xanthine, then urate + superoxide anion
  • superoxide anion (O2-) –> superoxide dismutase –> H2O2 (hydrogen peroxide)
  • superoxide anion + nitric oxide (NO) –> peroxynitrite (ONO-2)
  • if free iron present: Fenton/Haber-Weiss reaction –> hydroxyl free radial + hydroxyl anion
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10
Q

What are the two main radicals causing lipid peroxidation?

A
  • peroxynitrite
  • hydroxyl free radical
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11
Q

What type of lipids are the major target for lipid peroxidation?

A

polyunsaturated free fatty acids (PUFA)

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12
Q

What are the most susceptible amino acid residues to oxidative stress?

A
  • cysteine and methionine
  • oxidation of the sulfhydryl groups –> forms disulphide bridges –> inactivate a range of proteins –> impairment of cellular signaling and metabolism
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13
Q

Fill in the blanks

A

catalase + glutathione peroxidase

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14
Q

Fill in the blanks

A
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15
Q

What cofactors are needed for xanthine-oxidase to metabolize hypoxanthine to uric acid?

A

NAD+ and O2

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16
Q

Fill in the blanks

A
17
Q

What are the 4 damaging effects peroxynitrite and hydroxyl radicals have?

A
  • lipid peroxidation
  • oxidative damage to DNA/RNA
  • loss of membrane selective permeability
  • protein degradation
18
Q

What are the clinical consequences seen in patients with ischemia reperfusion injuries?

A
  • hyperkalemia
  • acidemia
  • cardiac arrhythmias
  • “no flow” phenomenom
  • myocardial stunning
  • central nervous system changes
  • GI signs
  • MODS
19
Q

Describe the “no flow” phenomenon in ischemia reperfusion injury

A

diminished or absent blood flow despite resolution of the vascular occlusion

neutrophil adhering to the endothelium –> induces endothelial swelling, platelet adhesion, thrombus formation + further neutrophil recruitment

20
Q

Describe the immunologic pathways of ischemia reperfusion injury

A
  • NF-kappa-B activation –> increase in inflammatory mediators + adhesion molecules (especially intracellular adhesion molecule-1 and E-selectin)
  • COX-2 activation –> proinflammatory prostaglandin formation + arachidonic acid + phospholipase A2 actrivation –> ROS
  • cell death –> DAMPs –> stimulates TLRs
21
Q

name 3 DAMPs released during cell death

A

cell-free DNA
histones
high mobility group box 1

22
Q

Name 8 antioxidant molecules

A
  • haptoglobin
  • ferritin
  • ceruloplasmin
  • vitamin C/ascorbic acid
  • glutathion
  • vitamin E/alpha-tocopherol
  • vitamin A/beta-carotene
  • ubiquinol-10
23
Q

how is arginine implicated in arterial thromboembolism formation?

A

low arginine levels –> increased platelet aggregation

24
Q

What are 3 ways to identify ischemia reperfusion injury?

A
  • measurement of reaction products, e.g., meondialdehyde (MDA) or isoprostanes
  • measurement of low levels of endogenous antioxidants, e.g., glutathione or tocopherol
  • measurement of biomarkers of injury, e.g., TNF-alpha, IL-1, IL-6, IL-8, transforming growth factor-beta, cell-free DNA
25
Q

What are effects of lidocaine besides Na-channel antagonism?

A
  • free radical scavenger (superoxide and hydroxyl radicals)
  • antagonist of ATP-sensitive potassium channels
  • inflammatory modulator
  • inhibitor of granulocytes
26
Q

Describe the evidence of lidocaine administration to reduce ischemia-reperfusion injury in dogs with GDV

A
  1. study administering lidocaine before surgery but after medical treatment (decrompression included) –> no benefit
  2. study administering lidocaine before decompression –> decreased incidence of AKI, cardiac arrhythmias, coag disorders and shortened hospitalization time
27
Q

List 7 proposed treatments for ischemia-reperfusion injuries

A
  • lidocaine
  • N-acetylcysteine
  • Ischemic preconditioning
  • deferoxamine
  • allopurinol
  • cyclosporine
  • remifentanil
28
Q

How is NAC proposed to help in ischemia-reperfusion injury?

A

Glutathione precursor that can penetrate into cells –> replenishes IC glutathione concentrations

29
Q

What is the mechanism of action of Deferoxamine in ischemia reperfusion injury?

A

Iron chelator

ischemia –> ferritin releases its bound Fe3+
superoxide + H2O2 –> mobilize iron from ferritin and heme

free iron –> Fenton/Haber-Weiss reaction

30
Q

What is the mechanism of action of Allopurinol in ischemia-reperfusion injury?

A

Xanthine-oxidase inhibtor

31
Q

How could cyclosporine help in ischemia-reperfusion injury?

A

calcineurin inhibitor

Calcineurin likely mediates Ca-trigger apoptosis in IRI

32
Q

What are the co-factors needed to convert H2O2 to hydroxyl free radicals?

A

Fenton/Haber-Weiss reaction!

Fe2+ (Ferrous ion)

Boards: Shock/Ischemia/CPR (7 decks)

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