The overall goal of this program since its inception has been to define the pathobiological response of the mammalian respiratory system to the inhalation of ambient concentrations of oxidant air pollutants. The focus of this renewal application will be on mechanisms of environmentally induced asthma in young children, using the model of environmental asthma in infant rhesus monkeys that the investigators have developed through the support of this program. Using this model over the previous five years of funding, the investigators have made a number of startling discoveries regarding the effect of chronic ozone exposure on lung development and growth during infancy, including: stunting of airway growth, postnatal loss of airway generations, impaired establishment of the fibroblast growth factor (FGF)-2 ternary signaling complex by basal cells, the failure of epithelial surfaces to innervate, impaired central nervous control, enhancement of the allergic response, airway hyperreactivity, disrupted alveolarization, and airway remodeling. The analytical framework in which all of the studies proposed for this renewal will be conducted is the epithelial/mesenchymal trophic unit (EMTU), whose cellular components establish trophic interactions via an extracellular signaling complex modulated by the basement membrane zone (BMZ). The overall hypothesis is that environmental exposure to oxidant air pollutants promotes the development of allergic asthma in the developing lungs of young children and exacerbates its severity by: 1) disrupting the homeostasis within the EMTU and 2) fundamentally compromising the establishment and differentiation of the trophic interactions that promote normal airway growth and development. These changes result from the superimposition of continual cycles of acute injury, inflammation, and repair on the immune response to allergen exposure. Each of the four projects within the program will focus on different components of the EMTU: Project 1, epithelial and mesenchymal cells (fibroblasts, smooth muscle) and the BMZ;Project 2, mucosal immune system;Project 3, innervation and neural control;and Project 4, vasculature.
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