The purpose of this application for renewal is to define the impact of exposure to bioactivated environmental contaminants on a special population: children. Lung disease is the leading cause of death in infants under one year of age and a strong relationship exists between human infant exposure to environmental air pollutants, increased respiratory infections in childhood and distal airway disease and asthma in adults. We have asked how exposure to bioactivated environmental lung toxicants affects neonatal lung growth and maturation. We have found 1) lungs of neonates are susceptible to acute injury by bioactivated Clara cell cytotoxicants at doses below the threshold for injury in adults and 2) once the acute cytotoxic injury occurs in neonates, repair is abnormal and incomplete, persisting even when the animals become adults. In this renewal, we propose to 1) characterize the normal pattern of airway growth and development focusing on extracellular signaling molecules known to be involved in injury and repair in the adult, 2) evaluate how repair of acute Clara cell injury conflicts with active airway growth to inhibit repair and the normal pattern of airway growth and development. We will use a comparative approach to discriminate the differences in normal growth and development when neonates are exposed to a P450-mediated toxicant. We have developed methods for quantifying airway growth in very small animals and will use this in combination with genetic and protein analysis to define the role of extracellular signaling molecules in airway growth and repair. This work will further our understanding of the basic molecular mechanisms by which environmental insults are involved in the origins of lung diseases that begin in childhood.
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