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 asthma in infant rhesus monkeys that the investigators have developed through the support of this program. Using this model over the previous five years of funding, the investigators 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 fibroblast growth factor (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 (EMTU), whose cellular components establish trophic interactions via an extracellular signaling complex modulated by the basement membrane zone (BMZ). The overall hypothesis 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 EMTU 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. Each of the four projects within the program will focus on different components of the EMTU: Project 1, epithelial and mesenchymal cells (fibroblasts, smooth muscle) and the BMZ;Project 2, mucosal immune system;Project 3, innervation and neural control;and Project 4, vasculature.
. Ozone is the principal oxidant air pollutant in most American cities. This program has found that exposure of infant rhesus monkeys to ozone and house dust mite allergen during the period of postnatal lung development impairs lung growth and development and results in allergic airways disease similar to that found in humans. The purpose of this renewal application is to use this model to determine how the air pollution in cities increases the risk of children for developing asthma or other chronic lung diseases.
|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|
|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|
|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|
|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|
|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|
|Herring, Matt J; Avdalovic, Mark V; Quesenberry, Cheryl L et al. (2013) Accelerated structural decrements in the aging female rhesus macaque lung compared with males. Am J Physiol Lung Cell Mol Physiol 304:L125-34|
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