An amphipathic alpha-helical decapeptide in phosphatidylcholine is an effective synthetic lung surfactant

An idealized model amphipathic alpha-helical decapeptide was synthesized and tested for efficacy as a totally synthetic lung surfactant in simple mixtures with dipalmitoylphosphatidylcholine (DPPC). Quasi-static lung compliance was restored to 92 +/- 3% of the unlavaged value at a pressure of 5 cm H2O in an in vitro lavaged rat lung model. A sustained improvement in gas exchange was also observed when guinea pigs were treated with the synthetic lung surfactant in an in vivo lavaged lung model. DPPC/peptide mixtures rapidly formed low surface tension films in the pulsating bubble surfactometer consistent with a mechanism in which the lipid and peptide mixture spreads rapidly in the lavaged lung to minimize the surface tension at the air/tissue interface. This decapeptide sequence is active in mixtures with DPPC whether the residues are in the all L or all D conformation. However, a peptide with identical sequence, but with alternating D and L amino acid residues, is relatively inactive. Positive charge interactions are not important since a peptide with formylated lysine residues is active. The activity of these decapeptides, with sequences unrelated to any of those in natural lung surfactants, shows that the classic amphipathic alpha-helical hypothesis may be useful in designing peptides that will be effective synthetic lung surfactants in binary mixtures with DPPC. The data demonstrate that a small water-soluble synthetic peptide containing an amphipathic alpha-helical structure combined solely with the major lipid of natural lung surfactant is effective in restoring lung compliance and gas exchange in surfactant-deficient lungs and may be useful in treatment of the respiratory distress syndromes.