Project 2 - Postnatal Development of Pulmonary Immune Mechanisms

University Of California At Davis, Davis CA

Investigators

Linked publications & trials

Abstract

The overall goal of this program since its inception has been to define the pathobiological response of the[unreadable] mammalian respiratory system to the inhalation of ambient concentrations of oxidant air pollutants.[unreadable] The focus of this renewal application will be on mechanisms of environmentally induced asthma in young[unreadable] children, using the model of environmental allergic asthma in infant rhesus monkeys that we have developed[unreadable] through support of this program. Using this model over the previous five years of funding, we have made a[unreadable] number of startling discoveries regarding the effect of chronic ozone exposure on lung development and[unreadable] growth during infancy, including: stunting of airway growth, postnatal loss of airway generations, impaired[unreadable] establishment of the FGF-2 ternary signaling complex by basal cells, the failure of epithelial surfaces to[unreadable] innervate, impaired central nervous control, enhancement of the allergic response, airway hyperreactivity,[unreadable] disrupted alveolarization, and airway remodeling. The analytical framework in which all of the studies proposed[unreadable] for this renewal will be conducted is the epithelial/mesenchymal trophic unit, whose cellular components[unreadable] establish trophic interactions via an extracellular signaling complex modulated by the basement membrane[unreadable] zone.[unreadable] The overall hypothesis for this program is that environmental exposure to oxidant air pollutants promotes the[unreadable] development of allergic asthma in the developing lungs of young children and exacerbates its severity by: (1)[unreadable] disrupting the homeostasis within the epithelial/mesenchymal trophic unit and (2) fundamentally compromising[unreadable] the establishment and differentiation of the trophic interactions that promote normal airway growth and[unreadable] development. These changes result from the superimposition of continual cycles of acute injury, inflammation,[unreadable] and repair on the immune response to allergen exposure.[unreadable] This Project will focus on mucosal immunity within the epithelial/mesenchymal trophic unit, with the following[unreadable] specific aims:[unreadable] 1) Determine how episodic ozone exposure in conjunction with sensitization to house dust mite (HDM)[unreadable] allergen can initiate the asthma phenotype during postnatal development.[unreadable] 2) Determine how episodic ozone exposure in conjunction with sensitization to HDM allergen can contribute[unreadable] to the progression of the asthma phenotype.[unreadable] 3) Determine how episodic ozone exposure in conjunction with sensitization to HDM allergen can result in[unreadable] persistence of the asthma phenotype into early adulthood.[unreadable]