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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 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