The introduction of surfactant for treatment of infants with Respiratory Distress Syndrome has been an important clinical advance. However, the mechanisms responsible for surfactant function at the molecular level remain incompletely understood. The basic hypothesis of this proposal is that hydrophobic surfactant proteins (SP-B and SP-C) have unique conformations that enable them to insert into lipid monolayers and bilayers in a manner that allows specific protein-protein and lipid-protein interactions that are important for optimal biological activity. Our work and that of others has led to the belief that under reducing conditions SP- B has a predominantly amphipathic alpha-helical structure that lies horizontally in the plane of a lipid monolayer. In contrast, SP-C is a very hydrophobic helical protein and has an orientation perpendicular to the plane of the lipid monolayer. Verification and refinement of these models requires understanding the effects of oxidation on monomers, palmitoylation of SP-C, conformations of the proteins in lipid, and the degree and angle of insertion of the proteins in lipids. A variety of spectroscopic techniques including circular dichroism (CD), Fourier transform infrared (FTIR), electron paramagnetic resonance (EPR), and nuclear magnetic resonance (NMR), as well as biophysical and physiological measures of surfactant function are proposed to address these questions. A unique aspect of this proposal is the use of synthetic proteins that emulate results found using native proteins. Animal studies of surfactant function include three different models of surfactant insufficiency or inactivation. These detailed studies should provide a better picture of the molecular architecture of surfactant lipids and the hydrophobic surfactant proteins and should help define synthetic lipid-peptide formulations that may further optimize surfactant therapy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL040666-07
Application #
2219692
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Project Start
1988-09-01
Project End
1996-03-31
Budget Start
1995-04-01
Budget End
1996-03-31
Support Year
7
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Pediatrics
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Boncuk, P; Kaser, M; Yu, Y et al. (1997) Effects of cationic liposome-DNA complexes on pulmonary surfactant function in vitro and in vivo. Lipids 32:247-53
Kaser, M R; Skouteris, G G (1997) Inhibition of bacterial growth by synthetic SP-B1-78 peptides. Peptides 18:1441-4
Gordon, L M; Horvath, S; Longo, M L et al. (1996) Conformation and molecular topography of the N-terminal segment of surfactant protein B in structure-promoting environments. Protein Sci 5:1662-75
Waring, A J; Faull, K F; Leung, C et al. (1996) Synthesis, secondary structure and folding of the bend region of lung surfactant protein B. Pept Res 9:28-39
Bruni, R; Fan, B R; David-Cu, R et al. (1996) Inactivation of surfactant in rat lungs. Pediatr Res 39:236-40
Findlay, R D; Taeusch, H W; David-Cu, R et al. (1995) Lysis of red blood cells and alveolar epithelial toxicity by therapeutic pulmonary surfactants. Pediatr Res 37:26-30
Putz, G; Goerke, J; Schurch, S et al. (1994) Evaluation of pressure-driven captive bubble surfactometer. J Appl Physiol 76:1417-24
Sehgal, S S; Ewing, C K; Richards, T et al. (1994) Modified bovine surfactant (Survanta) versus a protein-free surfactant (Exosurf) in the treatment of respiratory distress syndrome in preterm infants: a pilot study. J Natl Med Assoc 86:46-52
Putz, G; Goerke, J; Clements, J A (1994) Surface activity of rabbit pulmonary surfactant subfractions at different concentrations in a captive bubble. J Appl Physiol 77:597-605
Putz, G; Goerke, J; Taeusch, H W et al. (1994) Comparison of captive and pulsating bubble surfactometers with use of lung surfactants. J Appl Physiol 76:1425-31

Showing the most recent 10 out of 23 publications