MECHANISM OF SPECIES DEPENDENT ENVIRONMENTAL LUNG INJURY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. A substantial proportion of the US population continues to be exposed to harmful air pollutants such as ozone (O3). Despite the many years and extensive number of research efforts, the mechanisms of exposure-related lung injury, the factors that govern susceptibility and the long-term health consequences of childhood exposures remain poorly understood. New evidence suggests that episodic O3 exposure of infant nonhuman primates results in profound alterations in lung growth, structure, and function, and exacerbates development of reactive airways disease. Because O3 reactions with constituents of the epithelial lining fluid (ELF) dictate generation of the local dose, we hypothesize that the age-, site-, cell-, and disease-specific susceptibilities to acute versus episodic O3 exposure result from differences in ELF-dependent interactions associated with spatial heterogeneities in the local dose coupled with differential regulation of the airway epithelial intracellular and ELF antioxidant pools. To test this hypothesis, which will further our understanding of the fundamental mechanisms of O3-related disruption of normal lung development, lung injury, and susceptibility; we have brought together an interdisciplinary research team that encompasses expertise in lung surface chemistry, pathobiology and quantitative morphology, dosimetry, and extrapolation modeling. We have designed a highly interactive program that utilizes non-human primates (rhesus monkeys) and involves four interdependent projects and three cores. Our initial goals are to characterize the ELF-mediated generation of the local dose across age, exposure history, and airway sensitization; define the mechanisms of age-dependent susceptibility in the postnatal lung; characterize the determinants of airway remodeling as a function of acute versus episodic exposures; develop non-invasive biomarkers of lung injury utilizing the nose as a sentinel; and, formulate models that predict health outcomes across lung growth and airway sensitization. The program spans from molecular interactions to the intact primate, is highly relevant to the goals of NIEHS, is anticipated to extend into the human population, and will substantially reduce the uncertainties regarding the health effects of oxidant air pollution in our childhood population.