The objective of this proposal is to understand the mechanisms of fluid transport in human fetal lung and how these processes are developmentally regulated. While it is known that the pulmonary epithelium is secretory during development, there have been few studies to determine the cellular mechanisms involved, and the genes and proteins regulating fetal lung fluid production are unknown. In preliminary studies with human fetal lung explants and alveolar epithelial cell monolayers, I have shown that fluid is secreted as early as the sixth week of gestation, this process involves chloride (C1) secretion, and secretion can be stimulated by beta agonists, prostaglandins and cAMP. I have shown that the cystic fibrosis transmembrane conductance regulator (CFTR) mRNA and protein are present in human fetal lung, and that cAMP stimulates fluid secretion in human fetal lung tissue explants, suggesting that the CFTR is involved in this process. To look at fetal lung fluid secretion on a molecular level, I will study the expression of the CFTR gene and protein in the fetal lung, characterize its distribution during lung development, and evaluate hormonal signals which may regulate CFTR gene expression. Hopefully, this work will lead to a better understanding of normal lung development, and neonatal and pediatric lung diseases in which altered fluid balance may be important such as RDS, bronchopulmonary dysplasia, wet lung, and cystic fibrosis.
