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Shock and CPCR > Ischemia Reperfusion Injury > Flashcards

Ischemia Reperfusion Injury Flashcards

1
Q

List some pathophysiological processes involved in IR?

A
  • Activation of neutrophils
  • platelets
  • cytokines
  • reactive nitrogen species
  • reactive oxygen species (ROS)
  • the coagulation system
  • the endothelium
  • the xanthine-oxido-reductase enzyme system
    Source: JVECC SOAR 2004
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2
Q

What are the most common syndromes associated with IR in veterinary medicine?

A

GDV, ATE, resus from haemorrhagic shock, organ transplantation (?), diaphragmatic hernia, head trauma, mesenteric torsion, intestinal incarceration, spinal cord trauma.
Source: JVECC SOAR 2004

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3
Q

What is a free radical?

A

a molecule with one or more unpaired electrons in the outer shell. Since not all of the species that cause oxidative injury are technically free radicals(i.e., hydrogen peroxide is not a free radical, but is a key player in oxidative damage), a more appropriate term is ROS. ROS can react with all biological molecules
Source JVECC SOAR 2004

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4
Q

What are ROS generating organelles adjacent to?

A

Antioxidant mechanisms - thought to be the most important inate defense against ROS damage
Source JVECC SOAR 2004

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5
Q

Why are ROS thought to effect lipids most frequently?

A

This is believed tobe due to lipids’ propensity to contain double bonds and their ubiquitous presence in cell membranes
Source JVECC SOAR 2004

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6
Q

What may occur when two radicals interact?

A

May result in a more damaging product than the original radical or may terminate the cycle of damage
An example is when nitric oxide (NO) combines with superoxide (O2-) creating peroxynitrite (OONO-), which is 2000 times more damaging than hydrogen peroxide (H2O2)
Source JVECC SOAR 2004

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7
Q

Describe lipid peroxidation

A

Occurs mainly by hydoxyl (OH-) or peroxynitrite.
They initiate lipid peroxidation by abstraction of a proton from the polyunsaturated fatty acid forming a peroxy-radical. This then goes on to attack other PUFA in the cell membrane, propagating a chain reaction until all substrate is destroyed or an antioxidant is encountered.
Source JVECC SOAR 2004

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8
Q

What are the consequences of lipid peroxidation?

A

severely damages cell membranes, causing alterations in
- enzyme systems
- receptors,
- ion channels
and increases permeability to calcium and other ions.
In addition, the products of lipid peroxidation are also thought to initiate inflammation, apoptosis, and inactivation of thiol-containing enzymes.
Source JVECC SOAR 2004

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9
Q

What are antioxidants?

A

defined as substances that can delay or prevent oxidation of lipids, DNA, or proteins.
Antioxidant proteins, such as albumin, haptoglobin, ferritin, and cerulo-plasmin are abundant in plasma.
Intracellular enzymatic antioxidants include superoxide dismutase(SOD), catalase, and glutathione peroxidase
Source: JVECC SOAR 2004

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10
Q

WHat is generally considered the first line defense against ROS formation?

A

Glutathione peroxidase synthesis

Source: JVECC SPAR 2004

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11
Q

How does glutathione act?

A

Reduces hydrogen peroxide to water
There are two forms, one catalyzes the conversion of hydrogen peroxide and lipid peroxides and requires selenium as a cofactor
The other form doesn’t need selenium, but only catalyzes the reduction of hydrogen peroxide.
Oxidative stress has been shown to be associated with a depletion of GSH
Source JVECC SOAR 2004

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12
Q

What is the second line defense against ROS?

A

Vitamin E (tocopherols and tocotrienols)

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12
Q

What is the second line defense against ROS?

A

Vitamin E (tocopherols and tocotrienols)

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13
Q

What is the action of vitamin E?

A

Vitamin E inhabits the lipophilic interior of the cell membrane, where the PUFAs are located, andis a chain-breaking scavenger, halting lipid peroxidation

When a wave of lipid peroxidation reaches vitamin E, it is oxidized to a free radical, sparing any adjacent PUFAs from oxidation.

 Vitamin C (ascorbicacid) then combines with the E radical forming a poorly reactive, water-soluble, vitamin C radical, and regenerating vitamin E. Vitamin C is the most abundant water-soluble antioxidant and it can directly scavenge ROS or regenerate vitamin E
Source JVECC SOAR 2004
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14
Q

does the length and magnitude of decreased blood flow corrolate with severity of ischemic injury?

A

Yes

Source: JVECC SOAR 2004

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15
Q

How is intracellular calcium increased in ischemia

A

Due to atp depletion, inactivation of ATP dependent calcium channels and an influx of calcium
Source JVECC SOAR 2004

16
Q

What are the consequences of increased intracellular calcium?

A

Causes both apoptosis and necrosis
Activates a protease (calpain) which converts xanthine dehydrogenase(XD) to Xanthine oxidase (XO).

XD is formed in health and doesn’t require o2 for the conversion of hypoxanthanine to uric acid whereas XO is formed in ischemia (due to calcium) and does require O2. Which is a roadblock bc there is no O2 in ischemia. This causes the buildup of XO and hypoxanthine (a breakdown product of atp)
Source JVECC SOAR 2004

17
Q

What other processes occur during ischemia?

A

Acitvation of nuclear factor kB (NFkB) –> increased inflammatory mediators –> synthesis of intracellular adhesion molecules (specifically ICAM-1 and E0selectin) –> increased leukocyte adhesion at site of injury.
inactivation of endothelial NO –> vasoconstriction.
Platlet aggregation
decreased NO bc of hypoxia
compliment activation
Source JVECC SOAR 2004

18
Q

Does ischemia or reperfusion cause more damage?

A

Reperfusion

19
Q

Where is the first area beleived to generate ROS in reperfusion?

A

The interface between blood and endothelum.
Xanthine oxidase mediated endothelial injury is a major factor in IR
Source JVECC SOAR 2004

20
Q

Describe xanthine oxidase mediated injury during reperfusion

A

When O2 is reintroduced allows the conversion of hypothanthine into uric acid and superoxide via xanthine oxidase.
A burst of ROS is seen in the first 10-30 seconds
This causes the formation of superoxide and hydrogen peroxide which in the presence of free iron –> hydroxyl radical (BAD)
Source JVECC SOAR 2004

21
Q

Why is unbound iron more present in IR than health

A

Is usually tightly regulated with virtually no free iron in health. during ischemia released from intracellularly due to acidosis and the direct action of superoxide and hydrogen peroxide.
Source JVECC SOAR 2004

22
Q

How may ROS damage be halted

A

ROS chain reaction will continue until the hydroxyl radical is scavenged, two radicals combine to form a non-reactive species, or the substrate is consumed
SOURCE JVECC SOAR 2004

23
Q

Why is the brain at risk for IR injury?

A

One of the least protected organs from ROS damage
- high concentration of unsaturated fatty acids (i.e.,perfect media for lipid peroxidation),
- a large iron storewith low metal binding capacity (i.e., perfect forgeneration of hydroxyl radical),
- low antioxidant capacity, and is incapable of neuronal regeneration
Source JVECC SOAR 2004

24
Q

Discuss nitric oxide synthesis and activity in IR

A

The endothelium produces both NO and endothelin.
During ischemia, endothelial transcriptionof endothelin, NO isthe end product of nitric oxide synthase (NOS), whichoccurs in several isoforms; inducible NOS (iNOS),endothelial NOS (eNOS), and neuronal NOS (nNOS).Arginine and molecular oxygen are required for NOsynthesis.
In health, low doses of NO cause vasodila-tion via cGMP-mediated vasodilation. In the large concentrations generated by iNOS, it has a cytotoxic effects, causing severe,non-responsive vasodilation.
NO and superoxiderapidly combine to form a toxic reaction product, peroxy-nitrite (ONOO-), which is highly reactive, readilyreacting with proteins, lipids, and DNA during times of inflammation.
Hypoxia induces the transcription ofiNOS, but because oxygen is required as a substrate forNO production is limited. Upon reperfusion and re-introduction of oxygen, there may be sustained increases in NO. During reperfusion, large bursts ofROS can cause depletion of NO when it binds super-oxide.

25
Q

How may activated neutrophils cause tissue injury in IR

A

via ROS synthesisduring the respiratory burst,
release of intrinsicproteolytic enzymes,
by physical obstruction ofcapillaries
Source JVECC SOAR 2004

26
Q

What is the difference between phase 1 and phase 2 neutrophil adhesion in IR?

A

The early phase appears to be mediated by PAF- and XO-derived hydrogen peroxide,whereas phase 2 neutrophil adhesion appears to bemediated by PAF as well as oxidants generatedintracellularly within the mitochondria.

Phase 1: constitutively expressed ICAM-1 and rapidly mobilized preformed P-selectin as well asupregulation of neutrophilic surface expression ofb2-integrins.

Phase 2: (NFkB) –> upregulation ofendothelial cell adhesion molecules. NFkB is normally present in the cytoplasm and must be translocated into the nucleus to elicit a response via transcription.

27
Q

What is the ‘no-reflow phenomena’

A

The process in which organ bloodflow is not re-established after a period of ischemia.
Occurs with longer periods of ischemia.
Thought ot be due to swollen endothelium, endothelial protrusions, andplatelet, fibrin thrombi and neutrophil adhesion.

28
Q

what are some limitations of using malondialdehyde (mda) as a marker of lipid peroxidation?

A

There are numerous problems withthis test. Up to 98% of MDA that reacts with TBARS isformed after collection, during the incubation period ofthe assay.
There is an inconsistent level of sensitivityand specificity when these tests are appliedin vivo.
MDA is not a specific product of lipid peroxidation. Itcan also be formed as a result of thromboxane syn-thesis
SOURCE JVECC SOAR 2004

29
Q

What is an isoprostane?

A

A breakdown product of ROS damage to arachidonic acid in cell membranes. highly sensitive and specific for oxidative damage
Source JVEcc SOAR 2004

30
Q

Why are ROS difficult to measure?

A

Very short half life

Source: JVECC SOAR 2004

31
Q

What are the aims of treating IR injury?

A
  • blocking the formation of ROS
  • scavenging ROS after they are formed
  • blocking neutrophils
  • preventing platelet activation
32
Q

Have current clinical trials shown efficacy in neutrophil blockade

A

No

33
Q

Where is glutathione synthesised and with what?

A

In all cells but 90% in the liver. In the liver precursors are cysteine and methionine. In other cells precursor is just cysteine.
Cysteine is the rate limiting precursor (hence the rational for NAC)
Source JVECC SOAR 2004

34
Q

What products may target the formation of ROS

A

Glutathione (antiox), Vit E (antiox), Vit C(antiox but may also increase free iron), Ubiquinol (antiox), Calcium channel blockers, allopurinol (XO inhibitor)

35
Q

how may superoxide dismutase (SOD) be both pro and anti-oxidant?

A

Exists on the extracellular surface. Conversts superoxide to hydrogen peroxide then catalase converts this to water (antioxidant).
If not enough catalase hydrogen peroxide will convert to hydrol radial (pro-oxidant).

36
Q

How may DMSO theroretically be of benefit?

A

Scavenges hydroxyl free radicals and can pass through cell membranes.
However has shown no clinical benefit and thought that levels needed to result in benefit may be cytotoxic to healthy cells.

Shock and CPCR (5 decks)

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