title: Activity and biophysical inhibition resistance of a novel synthetic lung surfactant containing Super-Mini-B DATK peptide.
abstract: Background/objectives. This study examines the surface activity, resistance to biophysical inhibition, and pulmonary efficacy of a synthetic lung surfactant containing glycerophospholipids combined with Super Mini-B (S-MB) DATK, a novel and stable molecular mimic of lung surfactant protein (SP)-B. The objective of the work is to test whether S-MB DATK synthetic surfactant has favorable biophysical and physiological activity for future use in treating surfactant deficiency or dysfunction in lung disease or injury. Methods. The structure of S-MB DATK peptide was analyzed by homology modeling and by FTIR spectroscopy. The in vitro surface activity and inhibition resistance of synthetic S-MB DATK surfactant was assessed in the presence and absence of albumin, lysophosphatidylcholine (lyso-PC), and free fatty acids (palmitoleic and oleic acid). Adsorption and dynamic surface tension lowering were measured with a stirred subphase dish apparatus and a pulsating bubble surfactometer (20 cycles/min, 50% area compression, 37 °C). In vivo pulmonary activity of S-MB DATK surfactant was measured in ventilated rabbits with surfactant deficiency/dysfunction induced by repeated lung lavages that resulted in arterial PO2 values <100 mmHg. Results. S-MB DATK surfactant had very high surface activity in all assessments. The preparation adsorbed rapidly to surface pressures of 46-48 mN/m at 37 °C (low equilibrium surface tensions of 22-24 mN/m), and reduced surface tension to <1 mN/m under dynamic compression on the pulsating bubble surfactometer. S-MB DATK surfactant showed a significant ability to resist inhibition by serum albumin, C16:0 lyso-PC, and free fatty acids, but surfactant inhibition was mitigated by increasing surfactant concentration. S-MB DATK synthetic surfactant quickly improved arterial oxygenation and lung compliance after intratracheal instillation to ventilated rabbits with severe surfactant deficiency. Conclusions. S-MB DATK is an active mimic of native SP-B. Synthetic surfactants containing S-MB DATK (or related peptides) combined with lipids appear to have significant future potential for treating clinical states of surfactant deficiency or dysfunction, such as neonatal and acute respiratory distress syndromes.
authors.affiliation: Department of Pediatrics, University of Rochester , Rochester, NY , United States.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Notter
authors.affiliation: Department of Pediatrics, University of Rochester , Rochester, NY , United States.
authors.forename: Zhengdong
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, David Geffen School of Medicine, University of California , Los Angeles, CA , United States.
authors.forename: Frans J
authors.initials: FJ
authors.lastname: Walther
keywords: Acute lung injury (ALI); Acute respiratory distress syndrome (ARDS); Neonatal respiratory distress syndrome (NRDS); SP-B peptide mimics; Super Mini-B; Super Mini-B DATK; Synthetic lung surfactant; Synthetic surfactant peptides