Oxidative Stress & Inflammation in a Human PM Nasal Challenge

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Asthma is a multifactorial, complex disease, which is exacerbated by multiple environmental factors. Findings from recent epidemiologic studies have suggested an association between both airborne particulate matter (PM)exposure and asthma morbidity. However, there have been very few human challenge studies demonstrating that direct application of PM to airways leads to airways inflammation. In addition, there is little understanding of the mechanisms by which PM might induce or potentiate human airways responses. The Center for Childhood Asthma in the Urban Environment's overall hypothesis is that: PM exposure ==> oxidative stress ==> airways inflammation ==> airways symptoms. If the oxidative stress pathway proves to play a key role in induction of airways inflammation, therapies targeting this pathway may prove to be efficacious in asthma. In the inner-city, where exposure to PM occurs concomitantly with allergen exposure, chronic exposure to PM may lower the threshold for developing airways symptoms upon exposure to mouse allergen, a clinically relevant allergen in the urban environment. Therefore, we hypothesize that PM exposure causes inflammatory airways responses, and potentiates airways responses to allergen in IgE-sensitized individuals with asthma. Further, we hypothesize that these inflammatory and physiologic effects are associated with PM-induced oxidative stress. To test these hypotheses, we will conduct nasal and bronchial challenges to PM and mouse allergen. The specific aims are:(1) To demonstrate that PM induces oxidative stress and inflammatory airways responses using an established nasal challenge model, (2) To determine if prior PM exposure enhances nasal responses to subsequent allergen challenge in IgE-sensitized adults with asthma, and (3) To determine if prior PM exposure enhances pulmonary responses to subsequent allergen challenge in IgE-sensitized adults with asthma. The results from these studies will impact asthma health by (1) informing environmental policy, (2) shaping future recommendations regarding environmental control practices, and (3) examining a mechanistic pathway that can be targeted in the development of novel asthma therapies in subsequent studies.