Oxidant Mechanisms in Response to Ambient Air Particles

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Oxidant Mechanisms in Response to Ambient Air
Particles Beatriz González-Flecha Department
of Environmental Health Harvard School of Public
Health Boston, MA, USA
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Oxygen toxicity early evidence
Mice
Mice
Drosophila
Rats
Paramecia
Rats
Paramecia
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Oxygen poisoning and X-irradiation A mechanism
in common R. Gershman et al. Nature,
1954 First demonstration of the involvement of
oxygen free radicals in the mechanism of oxygen
toxicity
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Oxygen Free Radicals Reactive Oxygen Species
(ROS)
e-
e-
e-
e-
O2-.
H2O2
HO
H2O
O2
Superoxide anion
Hydrogen peroxide
Hydroxyl radical

• Produced in association to aerobic
• metabolism (1952)(1970s)

• Able to promote cell proliferation and
• enzyme induction at sublethal
• concentrations (1962)(1990)

• Toxic at high concentrations (1954)
• (1970s)

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Main sources of ROS in mammalian
tissues Intracellular source Species 1.
Mitochondrial Respiratory Chain Ubiquinone
O2-. NADH dehydrogrenase O2-. 2.
Enoplasmic Reticulum NADH-cytochrome reductase
O2-. or H2O2 Cytochrome P450
O2-. Cytochrome b5 O2-. 3. Plasma
Membrane Lipoxygenase 1O2 Prostaglandin
synthase 1O2 NADH oxidase (PMN) O2-. 4.
Cytosol a) soluble enzymes and
proteins Hemoglobin O2-. Xanthine
oxidase O2-. b) small molecules Flavins
O2-. or H2O2 Thiols O2-.
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Radical Chain
Protective mechanisms


O
2
SOD
10 -11 M

O
-

O
H
O
2
2
2
2
Catalase
10 -7 M
H
O
O
H
O
2
2
2
2
HO

Carotene
10 -13 M
1
O
O
2
2
Modified from Chance et al. Physiol. Rev. 59,
527-605 (1979).
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Radical Chain
Protective mechanisms


O
2
SOD
Damage to cellular components

O
-

O
H
O
2
2
2
2
Catalase
H
O
O
H
O
2
2
2
2
HO

Carotene
1
O
O
2
2
Modified from Chance et al. Physiol. Rev. 59,
527-605 (1979).
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Pulmonary Responses to Oxygen
20 O2 Normoxia
85 O2 Adaptive responses
Proliferation of epithelial cells
Induction of antioxidant enzymes
100 O2 Damage to the lung epithelium
Inflammation Edema
Post-100 O2 Reparative responses Epithelial
remodeling Enzyme induction
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Cellular Responses to ROS
ROS concentration
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Health Effects of Ambient Air Particles
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1943- Los Angeles, CA Visibility 3 Blocks.
Numerous complaints watery eyes, nausea,
respiratory discomfort
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20 People and 1,000's animals dead, 6,000 ill
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1952- London, England 4,000 Dead
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Ambient air particles have intrinsic toxicity
Particle pollution, and not other pollutants,
leads to increased death across much of the USA
(HEIwww.healtheffects.org.news)
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• Particle Sources
• Anthropogenic sources
• Transportation
• Power plants
• Incinerators
• Wood burning
• Natural Sources
• Volcanoes
• Erosion
• Forest fires
• Sea spray
• Soil
• Biological (pollen, spores)

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Ambient Air Particles and Oxidants

• CAPs increase luminol-enhanced
  chemiluminescence, and the oxidation of
  redox-sensitive fluorescent markers in PMN and
  alveolar macrophages in vitro

• Quinone radicals were detected in air particles
  _at_ 1010 per mg

• PM inhalation induces anti-oxidant enzymes

• Oxidants induce expression of pro-inflammatory
  cytokines

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Mechanism of Pulmonary Oxidative Stress and
Toxicity by PM
Particle/cell interactions Direct action on
intracellular sources of ROS
Potentiation by macrophage-derived
cytokines TNF-alpha, IL-8, etc.
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Cardiac Effects of PM
Neural mechanisms sympathetic/parasympathetic
stimulation of the heart
Inflammatory mechanisms release of
cytokine/chemokine into circulation
Direct action on the heart Soluble components
(inorganic and organic) Insoluble
(ultrafine/fine particles)
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Summary

• The health effects of PM in humans as well as
  the biological effects of CAPs in animal and cell
  models are well documented
• The existing evidence strongly suggests that
  ROS are involved in the initiation steps of the
  mechanistic pathways leading from PM exposure to
  inflammatory effects and cardiopulmonary toxicity
  
• The cellular mechanisms of PM toxicity are
  currently under investigation