Download Oxygen toxicity

Oxidant Mechanisms in
Response to Ambient Air
Particles
Beatriz González-Flecha
Department of Environmental Health
Harvard School of Public Health
Boston, MA, USA
Oxygen
toxicity:
Mice
early
evidence
Mice
Drosophila
Rats
Paramecia
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-
O2-.
Superoxide
anion
e-
H2O2
e-
Hydrogen
peroxide
HO•
e-
Hydroxyl
radical
• Produced in association to aerobic
metabolism (1952)(1970’s)
• Able to promote cell proliferation and
enzyme induction at sublethal
concentrations (1962)(1990)
• Toxic at high concentrations (1954)
(1970’s)
H2O
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
1O
Lipoxygenase
2
1O
Prostaglandin synthase
2
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-.
Radical Chain
Protective mechanisms
O2
10
-11
10
-7
M
M
O
2
•-
H 2O 2
10
M
1O
O 2 + H 2O 2
Catalase
O 2 + H 2O
•
HO
-13
SOD
Carotene
2
O2
Modified from Chance et al. Physiol. Rev. 59, 527-605 (1979).
Radical Chain
Protective mechanisms
O2
O2
•-
H 2O 2
SOD
O 2 + H 2O 2
Catalase
O 2 + H 2O
•
HO
Carotene
1O
2
O2
Modified from Chance et al. Physiol. Rev. 59, 527-605 (1979).
Pulmonary Responses to Oxygen
20% O2
Normoxia
85% O2
Adaptive responses:
Proliferation of epithelial cells
Induction of antioxidant enzymes
100 % O2
Post-100% O2
Damage to the lung epithelium
Inflammation
Edema
Reparative responses:
Epithelial remodeling
Enzyme induction
ROS concentration
Cellular Responses to ROS
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
Transportation
Power plants
Incinerators
Wood burning
• Natural Sources
Volcanoes
Erosion
Forest fires
Sea spray
Soil
Biological (pollen, spores)
Ambient Air Particles and Oxidants
•
CAPs increase luminol-enhanced
chemiluminescence, and the oxidation of redoxsensitive 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 interactions
Direct action on intracellular sources of ROS
Potentiation by macrophage-derived cytokines
TNF-alpha, IL-8, etc.
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)
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