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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08HL002767-01
Application #
3083172
Study Section
Research Training Review Committee (RTR)
Project Start
1992-07-08
Project End
1997-06-30
Budget Start
1992-07-08
Budget End
1993-06-30
Support Year
1
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Iowa
Department
Type
Schools of Medicine
DUNS #
041294109
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Lamb, F S; Graeff, R W; Clayton, G H et al. (2001) Ontogeny of CLCN3 chloride channel gene expression in human pulmonary epithelium. Am J Respir Cell Mol Biol 24:376-81
Graeff, R W; Wang, G; McCray Jr, P B (1999) KGF and FGF-10 stimulate liquid secretion in human fetal lung. Pediatr Res 46:523-9
Watanabe, S; Matsushita, K; Stokes, J B et al. (1998) Developmental regulation of epithelial sodium channel subunit mRNA expression in rat colon and lung. Am J Physiol 275:G1227-35
Matsushita, K; McCray Jr, P B; Sigmund, R D et al. (1996) Localization of epithelial sodium channel subunit mRNAs in adult rat lung by in situ hybridization. Am J Physiol 271:L332-9
Zhou, L; Graeff, R W; McCray Jr, P B et al. (1996) Keratinocyte growth factor stimulates CFTR-independent fluid secretion in the fetal lung in vitro. Am J Physiol 271:L987-94
Stewart, B; Zabner, J; Shuber, A P et al. (1995) Normal sweat chloride values do not exclude the diagnosis of cystic fibrosis. Am J Respir Crit Care Med 151:899-903
McCray Jr, P B; Armstrong, K; Zabner, J et al. (1995) Adenoviral-mediated gene transfer to fetal pulmonary epithelia in vitro and in vivo. J Clin Invest 95:2620-32
McDonald, F J; Snyder, P M; McCray Jr, P B et al. (1994) Cloning, expression, and tissue distribution of a human amiloride-sensitive Na+ channel. Am J Physiol 266:L728-34
McCray Jr, P B; Bettencourt, J D; Bastacky, J et al. (1993) Expression of CFTR and a cAMP-stimulated chloride secretory current in cultured human fetal alveolar epithelial cells. Am J Respir Cell Mol Biol 9:578-85