This proposal will determine the mechanisms by which pulmonary surfactant adsorbs to an air-water interface. Surfactant is the mix of lipids and proteins that coat the thin liquid layer which lines the alveoli. The thin film of surfactant lowers the surface tension of the air-water interface and minimizes collapse of the small air spaces. Premature babies born without adequate levels of surfactant frequently die from respiratory failure unless treated with exogenous surfactant. Adults with abnormal surfactant might also benefit from therapeutic surfactant, but the most effective agents currently are unavailable in sufficient quantities. Understanding the activity of native surfactant may direct efforts to develop inexpensive artificial agents. To function effectively, pulmonary surfactant must adsorb rapidly to the air-water interface. Surfactant preparations that function well when spread artificially at an interface are ineffective in the lung if they adsorb slowly. Our previous results suggest that adsorption occurs in a series of distinguishable steps that include the initial juxtaposition of vesicles to the interface, the subsequent insertion of vesicles into the interface, and a late acceleration of adsorption during which surfactant somehow interacts cooperatively to produce faster rates. Our data suggest that insertion into the interface occurs via a tightly curved structure intermediate between the vesicle and the interface, and that the thermodynamic barrier to adsorption is the unfavorable enthalpy caused by the separation of acyl chains in the tightly bent lipid lamellae.
The specific aims will test hypotheses that follow directly from this general model. We will compare the effect of different surfactant components and of extrinsic factors at different stages of adsorption and in the vesicles or in preexisting monolayers on the kinetics and the components of the thermodynamic barrier to adsorption to determine if they function by the same or different mechanisms. We will use Brewster angle microscopy to monitor unadsorbed material adjacent to the interface and fluorescence microscopy to follow the composition of the adsorbed film.
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| Chavarha, Mariya; Khoojinian, Hamed; Schulwitz Jr, Leonard E et al. (2010) Hydrophobic surfactant proteins induce a phosphatidylethanolamine to form cubic phases. Biophys J 98:1549-57 |
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