Approximately half of the US population continues to be impacted by pathogenic air pollutants such asozone (O3), which recent epidemiologic studies suggest induces long term functional impairments inchildren. The mechanisms of exposure-related lung injury and how age and exposure history govern acuteand chronic susceptibility in the post natal lung remain poorly understood. Novel evidence documents thatpostnatal, episodic O3 exposure profoundly alters lung growth, structure, and function in non-humanprimates. Biological effects are likely determined by the combination of O3 intrapulmonary dispersion andreaction/diffusion within the epithelial lining fluid (ELF), leading to generation of the local dose. The overallhypothesis of this program is that the age-, site-, cell-, and exposure history-related susceptibilities to acuteversus episodic O3 result from differences in ELF-dependent interactions associated with spatialheterogeneities in the local dose coupled with differential regulation of the airway epithelial intracellular andELF antioxidant pools.Project 2 focuses on the tracheobronchial airways. The overall hypothesis being addressed by Project 2 isthat four characteristics of immature airways contribute to the heightened susceptibility of infants to oxidantexposure: 1) immature airway structure and cellular organization; 2) alterations in thickness of the epitheliallining layer; 3) local differences in levels of cellular and extracellular antioxidants; and 4) airway specificdifferences in the ability to generate an inflammatory response.Project 2 will pursue three specific aims:1) Determine the impact of age-related differences on this site specific pattern of injury and inflammationfollowing an acute episode of ozone exposure;2) Determine if ozone exposure during the postnatal period of lung development alters the site specificpattern of injury and inflammation found after an acute episode of ozone exposure later in life;3) Define the impact of ozone exposure during the postnatal period of lung development on the ability ofairways to mount an acute inflammatory response to bacterial lipopolysaccharide (LPS) later in life.Our efforts will advance understanding of the fundamental mechanisms of O3-related disruption of normallung development, lung injury, and susceptibility; and generate unique characterizations of lung structureand biochemistry.
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