Project 3 - Postnantal Development of Airway Neural Control

点击翻译按钮获取中文摘要

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 allergic asthma in infant rhesus monkeys that we have developed through support of this program. Using this model over the previous five years of funding, we 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 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, whose cellular components establish trophic interactions via an extracellular signaling complex modulated by the basement membrane zone. The overall hypothesis for this program 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 epithelial/mesenchymai trophic unit 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. This Project will focus on innervation and neural control within the epithelial/mesenchymal trophic unit, with the following specific aims: 1) Determine the impact of O3 and/or house dust mite (HDM) allergen inhalation on the sensory innervation of the conducting airways, its relation to growth factors and cues within the epithelial/mesenchymal trophic unit 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 arising from multiple airway generations and structures during critical windows of postnatal development and determine whether these changes persist into adult life. 3) Determine the critical window of susceptibility when exposure to O3 and/or HDM allergen results in persistent changes in smooth muscle contractility due to altered neural control. 4) Determine how the early and continued alteration in the balance between sympathetic and parasympathetic nerve activity to airway-associated lymph nodes modulates antigen recognition and lymphocyte phenotype and determine whether this modulation persist into adult life.