Numerous studies have shown a strong association between exposure to airborne particulate matter (PM) and indicators of asthma. However, the mechanisms underlying this association remain unknown. Utilizing murine strains of mice, we have demonstrated that exposure to real world particulate matter induces allergic responses in some strains (A/J) of mice, while not in others (C3H/HeJ). Our preliminary studies suggest that PM exposure may confer susceptibility to asthma symptoms by altering dendritic cell (DC) phenotype and function. Specifically, we have made the novel observation that PM alters the relative proportion of immunogenic myeloid DC to tolerogenic plasmacytoid DC recruited to the lungs of susceptible A/J mice. Although the mechanisms by which AUB regulates DC function are unknown, our preliminary data suggests the following hypothesis: that ambient PM induces the allergic response via activation of dendritic cells through synergistic oxidant and pattern recognition receptor- dependent (PRRs) pathways. To test this hypothesis, we propose the following aims: 1) To determine the molecular mechanisms by which PM-induces epithelial cell chemokine production and DC recruitment, we will test the hypothesis that PM induces epithelial cell chemokine production and DC recruitment and maturation via oxidative stress pathways;2) To determine the exact mechanisms by which PM alters DC cell phenotype, maturation and T cell stimulatory ability in vitro, we will evaluate the contribution of oxidative stress and pattern recognition receptor pathways (TLRs and dectin-1) to PM- induced alterations in DC phenotype (DC subset, costimulatory molecule expression, cytokine production, stimulation of CD4+T cells) in susceptible and resistant murine strains using a combination of approaches (i.e. pharmacological inhibitors, genetically engineered mice);and 3) To determine the contribution of AUB-activated DC subsets to susceptibility to the development of allergic airway responses in murine strains (A/J, C3H) in vivo, we will test the hypothesis that genetic differences in activation of oxidant and/or pattern recognition receptors (TLRs, dectin-1) contribute to altered activation of DC and subsequent development of the AUB-induced allergic phenotype. Taken together with the results of the other projects, the results of this proposal will provide a better understanding of how exposures to environmental particulate matter may exacerbate and/or induce airway inflammation and respiratory morbidity with the ultimate goal of translation of information into clinical applications or intervention strategies that can be used to reduce the morbidity of childhood asthma.
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