Epidemiological data demonstrate associated increases in particulate matter (PM) with increases in acute asthma exacerbations and risk of developing asthma;however, the reasons for these increases are poorly understood. We seek to establish the mechanism by which exposure to PM from Superfund sites modulates pulmonary immune homeostasis and results in the development of asthma. Asthma affects 300 million people worldwide, and its prevalence has been steadily increasing. The presence of a newly realized class of pollutants, environmentally persistent radicals (EPFRs), in contaminated soils at Superfund sites and PM from combustion and thermal treatment of hazardous substances suggests a potentially unrecognized risk factor for the development and/or exacerbation of asthma. We demonstrate that acute inhalation exposures to EPFRs in rodents initiate inflammatory responses in the lung characterized by an influx of neutrophils, occlusion of alveolar spaces, and increased bronchial hyperreactivity;all of which are indicative of severe asthma in humans. This occurs concurrently with the influx of both CD4+ and CD8+ lymphocytes and of dendritic cells (DCs) into the lung. Since DCs orchestrate many pulmonary immune responses, we believe they play a major role in EPFR-associated lung disease. This led us to the overall hypothesis: particle associated EPFRs initiate immunological changes that predispose to asthma by altering dendritic cell (DC) function such that Th17 responses are favored. To test this, we propose three aims.
Aim 1 will define the immunological and pathophysiological impact of acute and chronic inhalation exposures to EPFRs in normal and diseased lungs.
Aim 2 will determine the significance of pulmonary DCs in the pathophysiological response to EPFR exposure.
Aim 3 will illustrate the role of the Thi 7 lymphocyte subset in EPFR-induced asthma. This work will significantly advance our understanding of DC responses to xenobiotics and DC-induced immunotoxicity. This project draws on the strong complementary skills, unique expertise and resources in LSU-SRP's tightly synergist group and depends heavily on the shared samples, knowledge, and technical proficiency provided by the Cores.
Our studies will provide insight into how contaminated soils and PM produced from thermal treatment affects the development and progression of inflammatory airways disease (i.e. asthma) and provide a rational framework for clinical studies of antioxidant and cytokine modulation strategies to prevent EPFR-associated disease exacerbation. These studies will have important implications for public health and environmental policy, since there are currently no rules or regulations for limiting or monitoring EPFRs in the environment.
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|Kiruri, Lucy W; Khachatryan, Lavrent; Dellinger, Barry et al. (2014) Effect of copper oxide concentration on the formation and persistency of environmentally persistent free radicals (EPFRs) in particulates. Environ Sci Technol 48:2212-7|
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|Hettiarachchi, Suraj U; Prasai, Bijeta; McCarley, Robin L (2014) Detection and cellular imaging of human cancer enzyme using a turn-on, wavelength-shiftable, self-immolative profluorophore. J Am Chem Soc 136:7575-8|
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