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