The major emphasis of this research is to synthesize bioisoteric, biotransformation-resistant analogs of phospholipid components of natural lung surfactant, and to characterize their in vitro surface activity and aerosol behavior, together with their physiologic effects on pulmonary mechanics and function. The ultimate aim is to develop synthetic surface active mixtures of defined composition, containing no protein constituents, which may be of utility for therapeutic use in the neonatal and adult Respiratory Distress Syndromes (RDS and ARDS). A secondary goal is to help develop basic surface activity-molecular structure correlates for surfactants. Three major classes of phospholipid-analogs are proposed for synthesis: di-ether phosphonate analogs (DEPA), ether-ester phosphonate analogs (EEPA), and ether-amide phosphonate analogs (EAPA). Analogs of these classes, resistant to enzymatic degradation (eg. phospholipases) would be synthesized with defined fatty acid chains (eg. 16:0/16:0;18:1/18:1) for three corresponding natural phospholipid headgroups, ie. phosphatidylcholine, phosphatidylglycerol and phosphatidylethanolamine. Because of their enzymatic resistance, and close structural analogy to biologic phospholipids, such analogs are expected to have a high therapeutic half-life at the alveolar interface, with minimal toxicity and antigenicity. The in vitro surface and aqueous phase properties of surfactant analogs will be characterized in comprehensive experiments including dynamic and equilibrium surface tension lowering, dynamic respreading, and adsorption to the air-water interface at physiologic temperature and humidity. In addition, aqueous phase behavior of analogs will be studied by Differential Scanning Calorimetry, and the properties of analogs in aerosols from ultrasonic and jet nebulization will be characterized. The physiologic effects of analogs will also be studied after delivery to animal lungs as single components, or as mixtures (including mixtures with DPPC, the major natural lung surfactant phospholipid. Two types of lungs will be used: i) Excised rat lungs made surfactant deficient at 37C by multiple lavage, and ii) premature lambs of 130 days gestation. The excised lung studies will be used to screen the effects of a large number of synthetic surfactant mixtures and delivery methods (aerosolization vs. intra-tracheal instillation), while premature lamb experiments will be used as a final standard to characterize the efficacy of the most promising analogs or mixtures in reversing surfactant deficient states in vivo.
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