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).
