Traffic-associated air pollution and respiratory viral infections (URIs) are well-documented, independent stimulants of asthma symptoms, and both are associated with significant asthma morbidity. There is growing laboratory and epidemiologic evidence to suggest that air pollution and URIs have interactive effects on the respiratory system. We have shown, in a prior epidemiologic study, that asthmatics with cold symptoms show more changes in lung function associated with prior exposure to high pollution than those without colds. However, the independent and interactive effects of pollutants attributable to diesel and other vehicular emissions and URIs on asthma exacerbation in children have not been extensively studied. We propose to test the general hypothesis that traffic-associated air pollution, specifically diesel exhaust, and respiratory viral infections combine to induce exaggerated airway responses in children with asthma. Two potential mechanisms of interaction will be evaluated: a) traffic-associated air pollution increases susceptibility to viral URI, and b) combined traffic pollutant exposure and URI elicits augmented inflammatory and oxidative stress responses leading to worse clinical asthma outcomes. To test this hypothesis of interaction, we propose these Specific Aims: 1. Compare asthmatic children living near highways with diesel truck traffic to those living distant from high volume roads for a) the frequency and characteristics of viral upper respiratory infections (URIs) and b) changes in nasal expression of viral adhesion proteins and interferons. 2. Prospectively evaluate the interactions between air pollution and viral upper respiratory infections on a) asthma morbidity, and b) markers of inflammation and oxidative stress. These hypotheses will be tested in a prospective study of a cohort of children with persistent asthma with extensively characterized exposure to diesel and other vehicular emissions. We will study the effects of diesel exhaust on incidence of viral infection and susceptibility to virus by evaluating nasal lavage specimens for viral infection, viral load, intercellular adhesion molecule (ICAM)-1, low-density lipoprotein receptor (LDL)-R, Toll-like receptor (TLR)-3, interferons (IFNs)-2, 3, and;mRNA and protein expression using RT-PCR and ELISA, respectively. We will characterize interactive effects of diesel exhaust and PCR-confirmed viral infection on asthma health outcomes (primarily: fluctuations in daily measures of forced expiratory volume in 1 second (FEV1) and frequency of self-reported wheezing). We will also evaluate the role of enhanced inflammation and oxidative stress in these interactions by assessing markers of early physiologic response to exposures: exhaled nitric oxide (eNO), urinary 8-isoprostane, and nasal inflammatory cytokines (interleukin- 8/CXCL8, IP-10/CXCL10, RANTES/CCL5). The proposed studies will provide insight into the underlying biologic mechanisms and public health impacts of diesel-virus interactions in aggravation of childhood asthma.
This project will evaluate the impact on the health of asthmatic children of two very common "real world" asthma triggers: air pollution (especially diesel and vehicular exhaust) and respiratory viral infections. Enhanced knowledge of the extent and mechanisms of the interactions of these triggers will: a) give a more complete view of the public health impact of air pollution, facilitating scientifically-based air quality and traffic emissions policy;and b) enhance our understanding of the pathophysiology of asthma, a complex disease affecting 22.2 million people in the United States, thus pointing the way towards targeted therapies and public health approaches.
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