Impact of Early Life Diesel Exposure on Immune Patterning and Lung Structure/Func

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DESCRIPTION (provided by applicant): Asthma, a chronic inflammatory disorder of the airways, is a major public health concern, especially in children, affecting > 9 million children (13%) in the U.S. alone. Studies point to air pollution, including traffic emissions, as playing a significant role in the development of asthma and expression of asthma symptoms. This current proposal is based on our recent findings in the Cincinnati Childhood Allergy and Air Pollution Study (CCAAPS) longitudinal birth cohort demonstrating that diesel exhaust particle (DEP) exposure during infancy conferred risk for wheezing in a dose-dependent fashion. Although the link between DEP exposure and wheezing/asthma outcomes has been reported in many studies, the mechanisms underlying this association remain unclear. Clearly, there is a critical time period in early life when exposures have a significant health outcome. Importantly, during this period, lung development is also occurring. Delineating the mechanisms by which exposure to air pollution and allergens early in life impact the long-term risk for asthma is important as these factors can be controlled. Children with asthma have a more rapid decline in lung function as they age compared to normal individuals and the observed loss in lung function occurs before the age of 6, suggesting that there may be a direct effect on lung development and structure, however the pathogenesis is unclear. Similarly, the immune system is developing over this same time period. There is increasing data that exposures can directly affect the immune system including the development of T regulatory cells. The primary goal of this proposal is to test the central hypothesis that exposure to DEP and allergens impacts immune patterning and function and lung morphogenesis in infants increasing the risk for asthma and allergic disease. In order to address this hypothesis, we will utilize genetically manipulated mouse models of environmental exposures and asthma. Aims will determine the impact of DEP and aeroallergen exposure on: 1) postnatal lung morphogenesis, structure, and function; 2) regulatory T cell development and function, allergic sensitization patterns, and lung inflammation; and 3) lung function, regulatory T cell patterns, and cytokine profiles in CCAAPS. All of the children in CCAAPS have quantified measures of their DEP exposure, as well as their exposures to allergens. CCAAPS is funded by NIEHS, and as part of CCAAPS, the children will have pulmonary function testing performed at age 7. The mechanisms by which DEP confers risk will be investigated in parallel in our experimental models and in samples collected from the CCAAPS cohort. This proposal brings together investigators with a strong track record in lung development and remodeling (Le Cras), childhood asthma/allergy and immune regulation (Khurana Hershey), and environmental exposures on human health (LeMasters). PUBLIC HEALTH RELEVANCE: Asthma is a major public health problem that continues to increase in prevalence, particularly in children. This study will determine mechanisms by which exposure to diesel exhaust particles and allergens impacts immune patterning and function and lung development in infants increasing the risk for asthma and allergic disease. (End of Abstract)