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Pathophysiology 2 > Oxidative Stress > Flashcards

Oxidative Stress Flashcards

1
Q

What is oxidative stress?

A

A chronic imbalance between levels of reactive oxygen species/reactive nitrogen species and endogenous antioxidant defences

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2
Q

What respiratory diseases are linked to oxidative stress?

A 
ARDS
Asthma
COPD
Pulmonary Hypertension
Pulmonary Fibrosis
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3
Q

Is all oxidative stress bad?

A

No, acute reactive oxygen species can be protective and promote adaptive responses

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4
Q

Is all free radical production is bad?

A

No, free radical production is required for host defences and cell function and signalling

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5
Q

When does oxidative stress lead to disease?

A

Chronic oxidative stress will lead to pathology

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6
Q

What is a free radical?

A

A species with one or more unpaired electrons that is free to partake in chemical bonds

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7
Q

What is a reactive oxygen species?

A

Species that are usually derived from O2 radicals (superoxide) which may or may not be radicals

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8
Q

What is a reactive nitrogen species?

A

Species that are usually derived from NO radicals which may or may not be radicals

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9
Q

What are the sources reactive oxygen species?

A 
Smoking
Industrial airborn pollution
Car exhaust fumes
Enclosed cooking fired
Ionising radiation
UV radiation
Coal mining
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10
Q

What are the most common cellular sources of reactive oxygen species?

A

NADPH oxidases
Mitochondria (upto 25% of cellular ROS - electron leakage)
Peroxidases (MPO, EPO)
Oxidases (Xanthine oxidase, DUOX)

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11
Q

Where are xanthine oxidases found?

A

Lung epithelial lining fluid
Sites of inflammation
Implicated in pathology of several cardiovascular diseases

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12
Q

Where is myloperoxidase (MPO) found?

A

Released by neutrophils for pathogen killing

makes phlegm and snot green

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13
Q

What do ROS do?

A 
Lipid damage (peroxidation)
Protein damage (modification)
DNA damage
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14
Q

How do ROS damage lipids?

A

Unsaturated fatty acids undergo addition of O2 in a chain-reaction.

Essentially this is akin to butter going rancid

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15
Q

How do ROS damage proteins?

A

Several amino acids can be modified. The most common are:
Cysteine or methionine oxidation
Tyrosine to dityrosine, nitrotyrosine, or chlorotyrosine
Protein carbonyl formation
Lysine adduction by lipid-oxidation products

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16
Q

How do ROS damage DNA?

A

Most common is 8-oxo-guanine.

Mutation occurs when DNA polymerase makes a mistake when replicating the damaged section

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17
Q

Define carbonyl stress

A

The increased burden in reactive carbonyl species resulting in protein modification

18
Q

What are the consequences of oxidative stress?

A 
Autoimmune induction
Pro-inflammatory signalling
Mucus hypersecretion
Bronchial constriction
Mitochondrial damage
Altered cell fate (Cancer/death)
Extracellular remodelling (fibrosis)
Muscle dysfunction
Impaired cell function (phagocytosis)
Impaired drug function (corticosteroid)
19
Q

How are ROS removed?

A 
Target the oxidative stress:
    Induce endogenous antioxidant defences
    Supplement antioxidants (pharmacological/dietary)
20
Q

What does myeloperoxidase do?

A

It makes hypochlorous acid (HOCl) from Cl- ions for pathogen killing

(A variant, eosinophil peroxidase, (EPO) prefers Br- ions, to make HOBr)

21
Q

What is the sequence of events in lipid peroxidation

A

Initiation (initial radical attack)
Propagation (addition of oxygen)
Cycling (fatty acid radical attacks adjacent fatty acid)
Lipid peroxide
Fragmentation (formation of Reactive Carbonyl Species)

22
Q

What is lipid peroxidation?

A

ROS mediated damage of lipids

23
Q

What fatty acids are affected by lipid peroxidation?

A

Affects polyunsaturated fatty acids in the lipid membranes

The most susceptible common fatty acids are:

  • Linoleic acid
  • Linolenic acid
  • Arachidonic acid
24
Q

What are the different sources of endogenous antioxidant defences?

A

Enzyme/protein antioxidants
Metal binding proteins
Chain breaking antioxidants
Antioxidant Response Element (ARE)

25
Q

List the different enzyme/protein antioxidants

A 
Superoxide dismutase (3 isoforms: cytosolic, mitochondrial, and extracellular)
Catalase
Glutathione peroxidase (many isoforms)
Caeruloplasmin (prevents Fenton chemistry)
Thioredoxin (acts like GSH)
26
Q

List the different Metal binding protiens

A

Transferin
Ferritin
Lactoferin

27
Q

List the different chain breaking antioxidants

A

Lipid phase:

  • Tocopherols
  • Ubiquinol
  • Carotinoids
  • Flavinoids

Aqueous phase:

  • Ascorbate
  • Urate (uric acid)
  • Glutathione and other thiols (Can also target carbonyls)
28
Q

Describe the properties of Glutathione (GSH)

A

It is an important extra and intracellular antioxidant throughout the body

It is a simple tripeptide

It conjugates and detoxifies electrophiles directly, or enzymatically (GST)

It maintains essential REDOX and thiol status of the cells and is involved in cysteine storage

29
Q

What determines protein susceptibility to Carbonyl stress

A

Concentration and half life of target protein
Is the target protein expressed at the site of oxidative/carbonyl stress
Can the protein be modified and where is the modification
Does modification impact on function (inactivate enzyme, increase or prevent degradation)

30
Q

What determines the outcome of Carbonyl stress?

A

Low level carbonylation tags proteins for proteosomal degradation

High level carbonylation inhibits the proteosome and cause accumulation of the dysfunctional protein

31
Q

Give examples of how oxidative stress can be measured

A

Measurement of glutathione (reduced and oxidised)
Measurement of total protein carbonyls
Immunoassay based detection of protein carbonyls

32
Q

Describe the features of the measurement of oxidative stress by measurement of glutathione

A

Colourimetric assay - quantitative
Measures both reduced and oxidised glutathione
GSSG levels indicate oxidative burden
GSSG/GSH ratio is a better measure of oxidative stress
Higher ration=more oxidative stress

33
Q

Describe the features of the measurement of oxidative stress by measurement of total protein carbonyls

A

Spectrophotometric DNPH assay - quantitative
Requires only 50ng of protein
Sensitivity ~ 1pmol

34
Q

Describe the features of the measurement of oxidative stress by immunoassay based detection of protein carbonyls

A

ELISA
Western blot
2D gel electrophoresis
Immunochemistry

35
Q

What are the 2 key enzymes involved in glutathione synthesis?

A

Glutamate-cysteine ligase

Glutathione synthetase

36
Q

What is the key enzyme involved in glutathione regeneration?

A

Glutathione reductase

37
Q

When is NF-E2 related factor 2 (Nrf2) active?

A

Nrf2 is only active when released for complex with KEAP1

38
Q

Describe the features of Nrf2

A

Nrf2 activity declines with age and COPD severity
Carbonyl stress reduces Nrf2 activity and expression
Nrf2 loss increases inflammation and pathology
- Cigarette smoke model: increases inflammation and pathology

39
Q

How does the body prevent oxidative stress?

A

Antioxidant and Carbonyl scavengers

40
Q

What is the clinical evidence for oxidative stress in airway disease?

A

Clinical evidence:

  • DIRECT: Smokers/Individuals exposed to high pollution/ROS most suscetable to developing COPD
  • DIRECT: increased ROS, RNS, TBARs, Carbonyls – correlate to disease severity
  • INDIRECT: increased MΦ & Neutrophil activity in COPD  release more ROS
  • INDIRECT: Reduced dietary anti-oxidant intake = decreased lung function
41
Q

What is the mechanistic evidence for oxidative stress in airway disease?

A

Mechanistic evidence

  • Chronic Smoke exposed mice/rats get COPD-like pathology (Inflammation & lung destruction)
  • Chronic O3 exposure in mice get COPD-like pathology (Inflammation & lung destruction)
  • Antioxidants protect from Cigarette smoke induced Inflammation & emphysema in mice
42
Q

What is the therapeutic based evidence for oxidative stress in airway disease?

A

Therapeutic based evidence……(Limited evidence)

  • NAC 600mg bid oral: Reduced exhaled H2O2 & exacerbation frequency (Various studies)
  • Erdosteine 300mg bid: Less exacerbations & hospitalisation, improved QoL
  • Anti-oxidant rich diet: Reduced COPD mortality risk & improved lung function (Various studies)

Pathophysiology 2 (7 decks)

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