Oxidant Mechanisms in Response to Ambient Air Particles Beatriz González-Flecha Department of...
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Transcript of Oxidant Mechanisms in Response to Ambient Air Particles Beatriz González-Flecha Department of...
Oxidant Mechanisms in Response to Ambient Air
Particles
Beatriz González-Flecha
Department of Environmental HealthHarvard School of Public Health
Boston, MA, USA
Rats
Mice
Paramecia
Oxygen toxicity: early evidence
Mice
Drosophila Rats
Paramecia
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
Oxygen Free Radicals = Reactive Oxygen Species (ROS)
O2
e- e- e- e-
O2-. H2O2 HO• H2O
• Produced in association to aerobic metabolism (1952)(1970’s)
• Toxic at high concentrations (1954) (1970’s)
• Able to promote cell proliferation and enzyme induction at sublethal concentrations (1962)(1990)
Superoxide anion
Hydrogen peroxide
Hydroxyl radical
Main sources of ROS in mammalian tissuesIntracellular source Species1. Mitochondrial Respiratory Chain
Ubiquinone O2-.
NADH dehydrogrenase O2-.
2. Enoplasmic ReticulumNADH-cytochrome reductase O2
-. or H2O2 Cytochrome P450 O2
-.
Cytochrome b5 O2-.
3. Plasma MembraneLipoxygenase 1O2
Prostaglandin synthase 1O2
NADH oxidase (PMN) O2-.
4. Cytosola) soluble enzymes and proteins
Hemoglobin O2-.
Xanthine oxidase O2-.
b) small moleculesFlavins O2
-. or H2O2 Thiols O2
-.
O 2
O 2•-
H 2O 2
HO •
1O 2
O 2 + H 2 O2 SOD
O 2 + H 2 OCatalase
CaroteneO2
Radical Chain
Protective mechanisms
10 -11 M
10 -7 M
10 -13 M
Modified from Chance et al. Physiol. Rev. 59, 527-605 (1979).
O 2
O 2•-
H 2O 2
HO •
1O 2
O 2 + H 2 O2 SOD
O 2 + H 2 OCatalase
CaroteneO2
Radical Chain
Protective mechanisms
Modified from Chance et al. Physiol. Rev. 59, 527-605 (1979).
Dam
age
to c
ellu
lar c
ompo
nent
s
Post-100% O2 Reparative responses:Epithelial remodelingEnzyme induction
Pulmonary Responses to Oxygen20% O2 Normoxia
85% O2 Adaptive responses: Proliferation of epithelial cells
Induction of antioxidant enzymes
100 % O2 Damage to the lung epithelium Inflammation Edema
Cellular Responses to ROS
RO
S c
once
ntra
tion
Health Effects of Ambient Air Particles
1943- Los Angeles, CA Visibility 3 Blocks. Numerous complaints watery eyes, nausea, & respiratory discomfort
20 People and 1,000's animals dead, 6,000 ill
1952- London, England
4,000 Dead
Ambient air particles have intrinsic toxicity Particle pollution, and not other pollutants, leads to increased death across much of the USA (HEI:www.healtheffects.org.news)
Particle Sources• Anthropogenic sources
TransportationPower plants Incinerators Wood burning
• Natural SourcesVolcanoes Erosion Forest firesSea spray Soil Biological (pollen, spores)
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 @ 1010 per mg
• PM inhalation induces anti-oxidant enzymes
• Oxidants induce expression of pro-inflammatory cytokines
Mechanism of Pulmonary Oxidative Stress and Toxicity by PM
Particle/cell interactionsDirect action on intracellular sources of ROS
Potentiation by macrophage-derived cytokinesTNF-alpha, IL-8, etc.
Cardiac Effects of PM
Neural mechanisms sympathetic/parasympathetic stimulation of the heart
Direct action on the heartSoluble components (inorganic and organic) Insoluble (ultrafine/fine particles)
Inflammatory mechanismsrelease of cytokine/chemokine into circulation
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