Pulmonary surfactant serves the primary function of lowering surface tension at the air-liquid interface in the lung, thereby preventing alveolar collapse at low lung volumes. Deficiency in surfactant production has been incontrovertibly linked to respiratory distress syndrome (RDS) in the neonate. Surfactant is a complex combination of phospholipids, cholesterol, and three families of lung-specific surfactant proteins. The surfactant protein found in greatest abundance is a glycoprotein of with a reduced MW of 26-38 KDa that has been designated SP-A. The two remaining surfactant proteins are very hydrophobic. These two proteins have MWs of 18 KDa and 5-8 kDa, and have been designated SP-B and SP-C, respectively. While the full range of functions of the surfactant proteins are not known precisely, it has been demonstrated that all three affect the surface tension-lowering properties of surfactant phospholipids. Since RDS is a condition caused by surfactant deficiency, understanding the factors that regulate expression of these proteins of surfactant in clearly important. The intent of this proposal is to determine the factors affect initiation of expression of the three surfactant proteins in the predifferentiated lung, along with the factors that cause acceleration of expression can be divided into three general groups: hormones and other soluble factors, epithelial cell-extracellular matrix interactions, and epithelial- mesenchymal interactions. We will evaluate response of fetal lung cells to these factors by several methods. These will include quantitation of content of the surfactant proteins and their mRNAsl, measurement of surfactant protein synthesis, determination of relative rates of specific surfactant proteins. The overall goal of this project is to determine which endocrine and paracrine influences regulate expression of SP-A, SP-B, and SP-C in the developing lung. Knowledge of how the surfactant proteins are regulated may result in new approaches for the prevention and treatment of RDS.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL045011-03
Application #
3363880
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Project Start
1990-07-01
Project End
1995-06-30
Budget Start
1992-07-20
Budget End
1993-06-30
Support Year
3
Fiscal Year
1992
Total Cost
Indirect Cost
Name
National Jewish Health
Department
Type
DUNS #
City
Denver
State
CO
Country
United States
Zip Code
80206
Gebb, S A; Shannon, J M (2000) Tissue interactions mediate early events in pulmonary vasculogenesis. Dev Dyn 217:159-69
Guilbert, T W; Gebb, S A; Shannon, J M (2000) Lung hypoplasia in the nitrofen model of congenital diaphragmatic hernia occurs early in development. Am J Physiol Lung Cell Mol Physiol 279:L1159-71
Shannon, J M; Gebb, S A; Nielsen, L D (1999) Induction of alveolar type II cell differentiation in embryonic tracheal epithelium in mesenchyme-free culture. Development 126:1675-88
Shannon, J M; Nielsen, L D; Gebb, S A et al. (1998) Mesenchyme specifies epithelial differentiation in reciprocal recombinants of embryonic lung and trachea. Dev Dyn 212:482-94
Rice, W; Shannon, J M; Burton, F et al. (1997) Expression of a brain-type cannabinoid receptor (CB1) in alveolar Type II cells in the lung: regulation by hydrocortisone. Eur J Pharmacol 327:227-32
Deterding, R R; Jacoby, C R; Shannon, J M (1996) Acidic fibroblast growth factor and keratinocyte growth factor stimulate fetal rat pulmonary epithelial growth. Am J Physiol 271:L495-505
Deterding, R R; Shannon, J M (1995) Proliferation and differentiation of fetal rat pulmonary epithelium in the absence of mesenchyme. J Clin Invest 95:2963-72
Shannon, J M (1994) Induction of alveolar type II cell differentiation in fetal tracheal epithelium by grafted distal lung mesenchyme. Dev Biol 166:600-14
Deterding, R R; Shimizu, H; Fisher, J H et al. (1994) Regulation of surfactant protein D expression by glucocorticoids in vitro and in vivo. Am J Respir Cell Mol Biol 10:30-7
Kalina, M; Mason, R J; Shannon, J M (1992) Surfactant protein C is expressed in alveolar type II cells but not in Clara cells of rat lung. Am J Respir Cell Mol Biol 6:594-600