MECHANISMS OF SURFACTANT INHIBITION

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DESCRIPTION (Applicant's Abstract): Lung surfactant is a surface-active material that lines the alveolar surface of the lung and is composed of -90 percent lipids and 5-10 percent surfactant proteins (SF-A, B, C, and D). SF-A and SP-D are complex, lung-specific glycoproteins which modulate surfactant metabolism and lung immunological defense. SP-B and SP-C are short hydrophobic proteins, responsible for the surface activity of clinical surfactants derived from bovine and porcine lungs. Because natural surfactant preparations vary considerably in protein composition and may expose recipients to immunogenic proteins and viral contamination, we have focused on the structural and functional characteristics of synthetic mimics of human SP-B and SP-C and the design of a standardized, reproducible surfactant preparation of controlled composition. Premature infants with respiratory distress syndrome (RDS) are surfactant deficient due to lung immaturity, but functional surfactant deficiency due to inhibition of lung surfactant in the alveolar space predominates in adult respiratory distress syndrome (ARDS). Our objective is to design synthetic surfactants that will resist various types of inhibition associated with ARDS. The proposed studies include the design, synthesis, structural characterization, and in vitro and in vivo surface activity testing of synthetic lung surfactant formulations composed of phospholipids and SP-B and SP-C mimic peptides for use in the treatment of lung surfactant deficiency, surfactant inhibition, and bacterial pneumonia. We propose to extend these synthetic peptide design efforts to the synthesis of disulfide linked SP-B and SF-C homodimers that are similar to native hydrophobic surfactant proteins. Since SP-B and SF-C interact in vitro and in vivo and SP-A decreases the inhibition sensitivity of surfactant preparations, we will assess the surface activity of formulations with synthetic SF-B and SP-C mimic peptides and native SF-A. Overall, these studies will facilitate the identification and development of novel, peptide containing lung surfactant formulations that should be useful for treating surfactant deficiency and surfactant inhibition in neonatal RDS and ARDS.