The overall goal of this program since its inception has been to define the pathobiological response of themammalian respiratory system to the inhalation of ambient concentrations of oxidant air pollutants. The focusof this renewal application will be on mechanisms of environmentally induced asthma in young children, usingthe model of environmental allergic asthma in infant rhesus monkeys that we have developed through supportof this program. Using this model over the previous five years of funding, we have made a number of startlingdiscoveries 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 FGF-2ternary signaling complex by basal cells, the failure of epithelial surfaces to innervate, impaired central nervouscontrol, enhancement of the allergic response, airway hyperreactivity, disrupted alveolarization, and airwayremodeling. The analytical framework in which all of the studies proposed for this renewal will be conducted isthe epithelial/mesenchymal trophic unit, whose cellular components establish trophic interactions via anextracellular signaling complex modulated by the basement membrane zone.The overall hypothesis for this program is that environmental exposure to oxidant air pollutants promotes thedevelopment of allergic asthma in the developing lungs of young children and exacerbates its severity by: (1)disrupting the homeostasis within the epithelial/mesenchymal trophic unit and (2) fundamentally compromisingthe establishment and differentiation of the trophic interactions that promote normal airway growth anddevelopment. These changes result from the superimposition of continual cycles of acute injury, inflammation,and repair on the immune response to allergen exposure.This Project will focus on the epithelial and mesenchymal cells (fibroblasts, smooth muscle) and the basementmembrane zone within the epithelial/mesenchymal trophic unit, with the following specific aims:1) Define the impact ozone and allergen exposure during postnatal development on the function of airwayepithelium as the principle reactive interface between the environment and the rest of theepithelial/mesenchymal trophic unit.2) Define the impact of ozone and allergen exposure during postnatal development on the function of thebasal cell-basement membrane zone-fibroblast complex as both a mediator and a source of extracellularsignaling between luminal epithelium and the matrix within the epithelial/mesenchymal trophic unit.3) Define the impact of oxidant and allergen exposure during postnatal development on the airway smoothmuscle as a responder to signaling from the basal cell-basement membrane zone-fibroblast complex andas a player in generating and maintaining the extracellular signaling milieu.
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