The purpose of this request 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 tobacco smoke, increased respiratory infections in childhood and distal airway disease and asthma in adults. Because most tobacco smoke components acquire the toxicity after metabolism by cytochrome P450 monooxygenases, we have asked how exposure to bioactivated lung toxicants affect neonatal lungs. We have found 1) lungs of neonates are susceptible to acute injury at doses below the threshold for injury in adults and 2) once the injury occurs, bronchiolar development and repair are abnormal and incomplete, even when the animals become adults. In this renewal request we propose to 1) define the mechanisms which render differentiating Clara cells in the immature lungs of neonates more susceptible to injury by bioactivated environmental contaminants and 2) identify the events that result in incomplete bronchiolar repair in injured neonates. We will use a comparative approach to discriminate mechanisms which are unique to a particular chemical class or mammalian species from those which apply to neonates in general. We will compare the injury and repair response of two compounds of different chemical classes and different pathways of activation and detoxification (naphthalene and 4-ipomeanol). We will compare neonates and adults of two species with differing levels of susceptibility as adults to these compound (mice and rabbits). Because we have found that differences in the location of the target epithelial population within the airways alters the injury and repair patterns, we have developed novel methodologies to specifically sample the subpopulations, biochemically analyze the metabolism and mRNA biology in their three-dimensional context. This work will further our understanding of the basic molecular molecular mechanisms by which environmental insults are involved in the origination of lung diseases that begin in childhood.
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