Therapeutic Surfactants

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 DESCRIPTION (provided by applicant): This proposal seeks to establish new methods for developing therapeutic surfactants. Pulmonary surfactant lowers surface tension in the lungs. In the absence of functional surfactant, breathing injures the thin barrier that separates alveolar ai from capillary lungs. In premature babies born before the lungs have adequate amounts of pulmonary surfactant, treatment with exogenous surfactants obtained from animal sources has significantly improved survival. These agents, however, have been unavailable in sufficient quantities for treatment of adults with disorders that also may involve abnormal surfactant. The proposed studies seek to provide the basis for designing inexpensive surfactants that could be used in adults. The two specific aims take different approaches to this problem. The first aim addresses the mechanisms by which the hydrophobic surfactant protein SP-B promotes the surfactant lipids to form an interfacial film. Rapid adsorption is the first step that pulmonary surfactant must accomplish to reduce surface tension. Factors that mimic this function of SP-B could then provide the basis for designing artificial surfactants. Our preliminary results suggest model in which the protein stabilizes a rate-limiting kinetic intermediate. The lipids of this hypothetical structure would form a stalk that extends from the adsorbing vesicle to the air/liquid interface. Each of the leaflets in the stalk would have negative curvature, defined by the concave shape of the hydrophilic face. Experiments will use X-ray scattering to determine if SP-B can make changes that would reduce the energy of bending required to form this structure, either by inducing more negative curvature or by making the leaflets more flexible. X- ray scattering will also locate the protein within the lipids to determine how they accomplish their structural and functional effects. The second aim will instead use mechanisms for promoting adsorption that are unavailable to native surfactant. Our preliminary results suggest a model for how preparations might achieve rapid adsorption by alternative mechanisms. The aim tests hypotheses generated by the model in experiments that correlate structures established by phosphorus-nuclear magnetic resonance and X-ray scattering with function obtained with both captive bubbles and excised lungs.