This research involves the study of lung surfactant (LS) from a multilevel perspective including: 1) the in vitro surface properties of LS and its major components; 2) the properties of surface active aerosols of LS and its components; 3) biochemical/biophysical correlations of composition and surface activity for LS from animal lung lavage and from type II cell cultures; and 4) the physiologic effects of LS mixtures delivered to surfactant deficient premature lambs and excised rat and ferret lungs to evaluate potential LS replacement therapy for infants with the neonatant Respiratory Distress Syndrome (RDS). In vitro surface property measurements to be made include dynamic surface pressure-area, adsorption, and dynamic relaxation. Equilibrium studies of surface pressure-concentration, sruface potential, and phase behavior by DSC, will also be used to help delineate component interactions related to physiologically important LS surface properties such as high dynamic surface pressure, rapid adsorption, and good respreading after film collapse. Biophysical/biochemical correlates of LS surface properties and composition will be done for LS from animal lung lavage and from type II cells in culture to further define essential system components. The particle size-distribution, humidity dependence, and surface activity of aerosols formed from mixtures of LS components by ultrasonic and jet nebulization will also determined. These broad spectrum in vitro studies will define specific LS component mixtures likely to be effective in exogenous replacement therapy for RDS. Promising mixtures will be studied further in two animal models: i) tracheal instillation or aerosolization of surface active mixtures to LS deficient premature lambs in vivo; and ii) instillation or aerosolization of mixtures into surfactant-deficient excised lungs from ferrets and rats. Experiments will attempt not only to define the most efficacious mixtures for LS replacement, but also to develop optimal delivery protocols (e.g., instillation versus aerosolization or a combination, best phospholipid dispersion method, the need for repeated doses, etc.). Finally, the proposed research includes studies of the surface and bulk phase interactions of LS with various blood plasma constituents (e.g., plasma proteins, enzymes, bilirubin) to help clarify the role of LS in the pathophysiology of lung injury states that lead to the Adult Respiratory Distress Syndrome (ARDS).

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL025170-05
Application #
3337977
Study Section
Biophysics and Biophysical Chemistry B Study Section (BBCB)
Project Start
1984-07-01
Project End
1987-06-30
Budget Start
1985-07-01
Budget End
1986-06-30
Support Year
5
Fiscal Year
1985
Total Cost
Indirect Cost
Name
University of Rochester
Department
Type
Schools of Medicine
DUNS #
208469486
City
Rochester
State
NY
Country
United States
Zip Code
14627
Notter, R H (1988) Biophysical behavior of lung surfactant: implications for respiratory physiology and pathophysiology. Semin Perinatol 12:180-212
Notter, R H; Shapiro, D L; Ohning, B et al. (1987) Biophysical activity of synthetic phospholipids combined with purified lung surfactant 6000 dalton apoprotein. Chem Phys Lipids 44:1-17
Notter, R H; Shapiro, D L (1987) Lung surfactants for replacement therapy: biochemical, biophysical, and clinical aspects. Clin Perinatol 14:433-79
Holm, B A; Notter, R H; Leary, J F et al. (1987) Alveolar epithelial changes in rabbits after a 21-day exposure to 60% O2. J Appl Physiol 62:2230-6
Holm, B A; Notter, R H (1987) Effects of hemoglobin and cell membrane lipids on pulmonary surfactant activity. J Appl Physiol 63:1434-42
Leary, J F; Finkelstein, J N; Notter, R H et al. (1986) A quantitative study of the development of type II pneumocytes in fetal lung. Cytometry 7:431-8
Notter, R H; Penney, D P; Finkelstein, J N et al. (1986) Adsorption of natural lung surfactant and phospholipid extracts related to tubular myelin formation. Pediatr Res 20:97-101
Holm, B A; Notter, R H; Siegle, J et al. (1985) Pulmonary physiological and surfactant changes during injury and recovery from hyperoxia. J Appl Physiol 59:1402-9
Holm, B A; Notter, R H; Finkelstein, J N (1985) Surface property changes from interactions of albumin with natural lung surfactant and extracted lung lipids. Chem Phys Lipids 38:287-98
Notter, R H; Egan, E A; Kwong, M S et al. (1985) Lung surfactant replacement in premature lambs with extracted lipids from bovine lung lavage: effects of dose, dispersion technique, and gestational age. Pediatr Res 19:569-77