Alarming increases in the incidence, morbidity and mortality from allergic asthma in children have been documented in the US over the last decade. The underlying cause(s) of this increase are unknown. Recent epidemiological studies have documented a positive association between levels of urban airborne particulate matter (PM) and exacerbations of asthma, although a causal relationship has not been established. Although virtually nothing is known about the mechanisms by which PM exposure may exacerbate asthma, PM exposure has been consistently shown to induce the production of the pro-inflammatory cytokine, interleukin-6 (IL-6). An immunopathogenic role for IL-6 in exacerbation of asthma may be hypothesized by the recent demonstration that it is critical in directing the development of allergin-driven pathogenic type-2 immune responses (IL- 4, IL-5) associated with asthma. The overall goal of this proposal is to establish a causal relationship between PM exposure and asthma morbidity and to determine the mechanisms by which PM elicits these effects. Thus, we plan to test the hypothesis that PM exposure exacerbates allergic asthma by inducing airway epithelial cell release of IL-6. To test this hypothesis, we have developed a unique murine model for susceptibility to allergic asthma. In this model, susceptible A/J mice develop antigen- dependent AHR eosinophilic inflammation and elevated IgE levels, concomitant with increases in lung levels of Th2 cytokine (IL-4), while resistant C3H/HeJ mice fail to develop these responses. Our preliminary data with this model, suggests that the asthmatic response in susceptible A/J mice is exacerbated by exposure to the reference emission source urban relationship between PM and allergic airway responses in genetically susceptible A/J mice. Secondly, we will determine the biological effects of PM exposure in non-allergic strains of mice. Thirdly, we will determine the role of IL-6 in mediating PM-induced inflammation and exacerbations of allergic asthmatic symptoms by neutralizing its activity in vivo and examining PM-induced effects on allergic airway responses. These studies will provide insight into the immunopathogenic mechanisms involved in PM- induced exacerbation of asthma and establish an exposure-response relationship upon which to base air quality standards to protect the health of asthmatic children living in urban environments.

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