DESCRIPTION: (Adopted from the Applicant's Abstract): Significant questions remain about the mechanisms by which pollutants, specifically particulate matter (PM), elicit adverse respiratory health effects. Airway epithelial cells are one of the first targets of ambient PM and are therefore an important model with which to investigate PM toxicity. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is one cytokine released by bronchial epithelial cells with a critical role in acute inflammation and immune regulation. GM-CSF has an important role in asthma and elevated levels of GM-CSF have been demonstrated in the airway of subjects with asthma. Murine models with epithelial cell transgene expression of GM-CSF also demonstrate allergic sensitization and the airway recruitment of eosinophils and dendritic cells (DC). Our laboratory has demonstrated GM-CSF production in association with upregulation of mitogen-activated protein kinase (MAPK) pathways in primary culture human bronchial epithelial cells (HBECs). Moreover, we now report that the fine/ultrafine (UF) fraction of urban ambient PM upregulates GM-CSF release by HBECs. These finding provoke basic questions about the intracellular signals by which GM-CSF in induced that PM effects in allergic asthma are mediated by the stimulated release of GM-CSF from bronchial epithelial cells and the creation of local cytokine environment that supports the recruitment and maturation of airway dendritic cells, leading to the initiation and perpetuation of an immune response to inhaled allergen. We now propose to address this hypothesis by three approaches: 1) Having previously demonstrated the release of GM-CSF by HBECs in response to the fine/UF fraction of urban ambient PM, we will now test the hypothesis that upregulation of GM-CSF in response to fine/UF PM requires activation of Raf isoforms and MAPK pathways that can be modified by the cytokine micro-environment (IL-4, IL-13, IL-5, TNF-alpha). 2) We will test the hypothesis that upregulation of GM-CSF expression in human bronchial epithelial cells is associated with specific chemical properties of the fine/UF fraction of ambient PM and will perform X-ray fluorescence and ion chromatography for principal component analysis. 3) We will test the hypothesis that inhalation of fine/UF ambient PM induces a GM-CSF-dependent recruitment and maturation of pulmonary DC in a murine model of cockroach Ag-induced airway sensitization.
NIH ExPorter
NIH ExPorter