title: An amphipathic alpha-helical decapeptide in phosphatidylcholine is an effective synthetic lung surfactant.
abstract: 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.
authors.affiliation: Marion Merrell Dow Research Institute Cincinnati, OH 45215.
authors.forename: L R
authors.initials: LR
authors.lastname: McLean
authors.forename: J E
authors.initials: JE
authors.lastname: Lewis
authors.forename: J L
authors.initials: JL
authors.lastname: Krstenansky
authors.forename: K A
authors.initials: KA
authors.lastname: Hagaman
authors.forename: A S
authors.initials: AS
authors.lastname: Cope
authors.forename: K F
authors.initials: KF
authors.lastname: Olsen
authors.forename: E R
authors.initials: ER
authors.lastname: Matthews
authors.forename: D C
authors.initials: DC
authors.lastname: Uhrhammer
authors.forename: T J
authors.initials: TJ
authors.lastname: Owen
authors.forename: M H
authors.initials: MH
authors.lastname: Payne
mesh_terms: D015060:1,2-Dipalmitoylphosphatidylcholine / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D004195:Disease Models, Animal; D004338:Drug Combinations; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008170:Lung Compliance / Q000187:drug effects; D008297:Male; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D010713:Phosphatidylcholines / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D011659:Pulmonary Gas Exchange / Q000187:drug effects; D011663:Pulmonary Surfactants / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D012131:Respiratory Insufficiency / Q000188:drug therapy / Q000503:physiopathology; D013329:Structure-Activity Relationship; D007507:Therapeutic Irrigation
chemical_list: D004338:Drug Combinations; D009842:Oligopeptides; D010713:Phosphatidylcholines; D011663:Pulmonary Surfactants; D015060:1,2-Dipalmitoylphosphatidylcholine