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/mesenchymal 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 mucosal immunity within the epithelial/mesenchymal trophic unit, with the following specific aims: 1) Determine how episodic ozone exposure in conjunction with sensitization to house dust mite (HDM) allergen can initiate the asthma phenotype during postnatal development. 2) Determine how episodic ozone exposure in conjunction with sensitization to HDM allergen can contribute to the progression of the asthma phenotype. 3) Determine how episodic ozone exposure in conjunction with sensitization to HDM allergen can result in persistence of the asthma phenotype into early adulthood.

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National Institute of Environmental Health Sciences (NIEHS)
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University of California Davis
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Crowley, Candace M; Fontaine, Justin H; Gerriets, Joan E et al. (2017) Early life allergen and air pollutant exposures alter longitudinal blood immune profiles in infant rhesus monkeys. Toxicol Appl Pharmacol 328:60-69
Hsia, Connie C W; Hyde, Dallas M; Weibel, Ewald R (2016) Lung Structure and the Intrinsic Challenges of Gas Exchange. Compr Physiol 6:827-95
Herring, Matt J; Avdalovic, Mark V; Lasley, Bill et al. (2016) Elderly Female Rhesus Macaques Preserve Lung Alveoli With Estrogen/Progesterone Therapy. Anat Rec (Hoboken) 299:973-8
Lynn, Therese M; Molloy, Emer L; Masterson, Joanne C et al. (2016) SMAD Signaling in the Airways of Healthy Rhesus Macaques versus Rhesus Macaques with Asthma Highlights a Relationship Between Inflammation and Bone Morphogenetic Proteins. Am J Respir Cell Mol Biol 54:562-73
Herring, M J; Putney, L F; St George, J A et al. (2015) Early life exposure to allergen and ozone results in altered development in adolescent rhesus macaque lungs. Toxicol Appl Pharmacol 283:35-41
Van Winkle, Laura S; Bein, Keith; Anderson, Donald et al. (2015) Biological dose response to PM2.5: effect of particle extraction method on platelet and lung responses. Toxicol Sci 143:349-59
Madl, Amy K; Plummer, Laurel E; Carosino, Christopher et al. (2014) Nanoparticles, lung injury, and the role of oxidant stress. Annu Rev Physiol 76:447-65
Herring, Matt J; Putney, Lei F; Wyatt, Gregory et al. (2014) Growth of alveoli during postnatal development in humans based on stereological estimation. Am J Physiol Lung Cell Mol Physiol 307:L338-44
Moore, Brian D; Hyde, Dallas M; Miller, Lisa A et al. (2014) Persistence of serotonergic enhancement of airway response in a model of childhood asthma. Am J Respir Cell Mol Biol 51:77-85
Murphy, Shannon R; Oslund, Karen L; Hyde, Dallas M et al. (2014) Ozone-induced airway epithelial cell death, the neurokinin-1 receptor pathway, and the postnatal developing lung. Am J Physiol Lung Cell Mol Physiol 307:L471-81

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