This application proposes studies to establish mechanisms by which pulmonary surfactant adsorbs rapidly to an air-liquid interface to form interfacial films capable of reducing surface tension during compression. Pulmonary surfactant reduces surface tension to extraordinarily low levels in the lung and is essential for normal respiration. Treatment with exogenous surfactant of premature infants born prior to the development of the surfactant system has increased survival by 50%. Although preliminary results suggest that this therapy is also effective in some adult disorders, the cost of the larger doses prohibits consideration of its standard use. The proposed research seeks to provide the basis for the design of inexpensive artificial surfactant by understanding mechanisms by which native surfactant lowers surface tension in lung. Adsorption to the air-liquid interface is a critical step in surfactant activity. The most prevalent component of surfactant, dipalmitoyl phosphatidylcholine (DPPC), lowers surface tension well when artificially spread interfacial films are compressed. But DPPC adsorbs to form these films extremely slowly. This research seeks to understand how the constituents other than DPPC facilitate adsorption of surfactant to form active interfacial films. The experimental design emphasizes the inclusion of minor components to ensure that important interactions are not ignored. Studies consider the effect of a range of specific components of surfactant in terms of an adsorption process which involves multiple steps. The bilayer vesicle in the liquid phase must convert to a monomolecular film at the interface, displace any preexisting films, and mature to become capable of lowering surface tension during compression.
The specific aims of the proposed research are: 1) to test the hypothesis that the rate of initial surfactant adsorption to a surface relatively devoid of interfacial monolayer is determined by the surfactant proteins, independent of lipids;; 2) to determine the effect of the hydrophobic constituents on the enthalpy and entropy of activation for initial adsorption to the air-liquid interface; 3) to test the hypothesis that the rate of surfactant adsorption to an interface with a preexisting film depends on the lipids present in the interfacial monolayer as well as proteins in the subphase vesicles; 4) to test the hypothesis that the adsorbed interfacial film matures to a form capable of reducing surface tension to low levels prior to undergoing compression.
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