Increases in ambient air particulate matter (PM) have been associated with increased morbidity in asthmatics and increased incidence or respiratory allergy. Exacerbation of house dust mite-induced allergic airway responses in the Brown Norway (BN) rat has been previously demonstrated in Dr. Gilmour?s laboratory with pre-sensitization exposure to residual oil fly ash, a PM constituent. Diesel exhaust particles (DEP) have been shown to increase 1) local mRNA expression of Th2 cytokines, 2) antigen-specific serum IgE levels and 3) T cell activation in mice and humans during allergic sensitization. In vitro studies in human bronchial epithelial cells have demonstrated production of the proinflammatory chemokines, IL-8 and RANTES, in response to DEP that is dependent on activation of the p38 MAP kinase signaling pathway but thought also to operate via NFkB activation. We seek to validate these findings in our in vivo rat model and provide a mechanistic link for DEP-induced enhancement of allergic sensitization using both in vivo and in vitro models. Our preliminary data demonstrate enhancement of allergic airway responses in BN rats exposed to DEP 24 hr prior to allergic sensitization. We hypothesize that DEP enhance pulmonary allergic sensitization by inducing the production of MIP-2 (IL-8 functional equivalent in the rat) and in turn promote T cell activation and recruitment in the airways by upregulating adhesion and co-stimulatory receptors on T cells. The proposed studies will contribute significantly to our knowledge of the cellular and molecular mechanisms by which DEP exacerbate respiratory allergy. The models established in these studies will provide tools for comparing animal and human responses to PM, potentially leading to the identification of targets for therapeutic treatments.
| DeMarini, David M; Brooks, Lance R; Warren, Sarah H et al. (2004) Bioassay-directed fractionation and salmonella mutagenicity of automobile and forklift diesel exhaust particles. Environ Health Perspect 112:814-9 |
