DEVELOPMENT AND DIFFERENTIATION OF AIRWAY EPITHELIUM

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The goal is to generate information that will enlarge our understanding of the perinatal development of the bronchiolar epithelium. This goal involves the pursuit of our long standing interest in Clara cell biology but includes the more recent expansion of this interest to studies of the regulation of the cellular composition of small conducting airways including our recent demonstration of a material present in bronchiolar-rich tissue of one day old rats that conditions medium to make it mitogenic in vitro for Clara cells of 14 day old rats. Thus we will: 1) based on studies already preformed test in rats the hpothesis that substances endogenous to lungs, perhaps in concert with systemic hormones, modulate Clara replication in a stimulatory or inhibitory manner; 2) test in rats clinically relevant perinatal perturbations (hyperoxia, hypoxia, prematurity, undernutrition) to determine if they modify the in vivo development of the bronchiolar epithelium, and, if they do, determine if "catch-up" normalization occurs, and investigate the mechanisms responsible for the normalization; 3) quantitate in humans the late prenatal and early postnatal developmental changes of the intracellular components of Clara cells and ciliated cells in small conducting airways and quantitate the developmental changes in the epithelial cell population of these airways. We think we can achieve these goals because most of the proposed experiments are based on extensive preliminary data we have developed and because we are our consultants have had extensive experience with most of the procedures and systems we propose to use. We believe our data will be useful to other investigators and clinicians and will substantially advance a clinically important but poorly understood and little studied area of respiratory biology.