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/mesenchymai 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 innervation and neural control within the epithelial/mesenchymal trophic unit, with thefollowing specific aims:1) Determine the impact of O3 and/or house dust mite (HDM) allergen inhalation on the sensory innervation ofthe conducting airways, its relation to growth factors and cues within the epithelial/mesenchymal trophicunit during critical windows of postnatal development, and whether these changes persist into adult life.2) Determine the impact of episodic O3 and/or HDM allergen inhalation on the sensory nerve activity arisingfrom multiple airway generations and structures during critical windows of postnatal development anddetermine whether these changes persist into adult life.3) Determine the critical window of susceptibility when exposure to O3 and/or HDM allergen results inpersistent changes in smooth muscle contractility due to altered neural control.4) Determine how the early and continued alteration in the balance between sympathetic andparasympathetic nerve activity to airway-associated lymph nodes modulates antigen recognition andlymphocyte phenotype and determine whether this modulation persist into adult life.
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