Cumulative epidemiological and experimental data have shown that exposure to air pollutants leads to increased cardiovascular morbidity and mortality, especially of ischemic nature. We have found that exposures to diesel exhaust and ambient ultrafine particles (PM<0.1 ?m) lead to dysfunctional HDL characterized by reduced antioxidant and anti-inflammatory vascular protective properties. The development of dysfunctional HDL correlates with increased lipid peroxidation in systemic tissues and increased formation of atherosclerotic lesions. We have also observed that diesel exhaust leads to activation of the 5-lipoxygenase (5-LO) pathway in the liver. In the last few years, remarkable progress has been made in determining a plethora of systemic effects induced by air pollution. However, many mechanistic details remain to be elucidated. The observations that particle uptake by alveolar macrophages significantly correlates with the development of atherosclerotic plaques strongly suggest these cells are likely mediators in translating effects from the lungs to the systemic tissues. Our overarching hypothesis is that exposure to ambient PM results in lipid peroxidation, dysfunctional HDL and enhanced atherosclerosis via the induction of systemic prooxidant and proinflammatory effects which are mediated by the activation of macrophages and lipoxygenase pathways. We will test this hypothesis via three specific aims: 1) To evaluate whether activation of the 5-lipoxygenase pathway mediates air pollution effects that promote lipid peroxidation, HDL dysfunction and atherosclerosis. We will use 5-LO knockout (KO) mice and 5-LO pharmacological inhibitors to evaluate whether systemic effects induced by diesel exhaust are ameliorated after 5-LO ablation. 2) To assess the role of alveolar and systemic macrophages in the enhancement of lipid peroxidation, HDL dysfunction and atherosclerosis induced by air pollutants. We will use macrophage-specific Heme oxygenase 1 (HO-1) KO mice to develop lung chimeric mice with ablated HO-1 and decreased antioxidant defense in their alveolar macrophages in order to evaluate the potential role of these cells as mediators of diesel exhaust-induced systemic effects. 3) To provide important """"""""real-world"""""""" corroboration of the relevance of the animal studies by evaluating the effects of subacute exposure to air particulate matter on HDL function in human subjects. We will explore if there are associations between the concentration levels of ambient PM and HDL antioxidant capacity in subjects residing in areas with low and high levels of air pollution. Determining potential mechanisms and whether PM exposure induces effects on HDL functionality in humans would be of enormous importance as they may inform on pathogenesis and could lead to identifying novel biomarkers of PM-mediated health effects.

Public Health Relevance

This project aims to understand the effects that exposure to air particulate matter produces on HDL function and atherosclerosis, an inflammatory process within the blood vessels that is initiated and propagated by the deposition of lipids and lipoproteins and that is the cause for cardiovascular ischemic diseases such as heart attacks and strokes, responsible for the largest number of deaths in the western world. Air pollution contains both gaseous and particulate components (particulate matter) and it appears that the latter ones are mostly responsible for its cardiovascular toxicity by promoting systemic oxidative stress and proinflammatory effects that result in the loss of HDL anti-inflammatory properties. This proposal is designed to explore the mechanisms whereby exposure to air particulate matter induces systemic lipid peroxidation, dysfunctional HDL and atherosclerosis, with the ultimate goal of helping to develop in the future, strategies that could allow inhibiting the toxic and harmful effects of air pollutants and/or stratify individual risk for toxicity.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
High Priority, Short Term Project Award (R56)
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Special Emphasis Panel (ZRG1-DKUS-C (90))
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Schug, Thaddeus
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University of California Los Angeles
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
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