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.
Highlights
When endogenous lung surfactant is deficient or becomes dysfunctional in humans, it can be replaced by exogenous surface-active substitutes
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 high in vitro adsorption and dynamic surface activity of 5:3:2 dipalmitoyl phosphatidylcholine (DPPC):POPC:POPG +3% S-MB DATK surfactant in the absence of inhibitor substances is summarized in Additional in vitro surface activity studies examined the ability of synthetic S-MB DATK surfactant to resist biophysical inhibition by substances that can be present in the lung alveoli or interstitium during inflammatory lung injury
Summary
When endogenous lung surfactant is deficient or becomes dysfunctional in humans, it can be replaced by exogenous surface-active substitutes. We have detailed the molecular design, synthesis and activity of Mini-B (MB) and Super Mini-B (S-MB) peptides, two active mimics of native SP-B (Waring et al, 2005; Walther et al, 2007; Walther et al, 2010). These two active peptides (34 and 41 residues, respectively) incorporate active amphipathic helices and the ‘‘saposin fold’’ (Bruhn, 2005) of human SP-B (i.e., helix— turn—helix), and S-MB includes the functionally important N-terminal insertion sequence of the native apoprotein. The major focus of this study is on documenting the high surface activity and biophysical inhibition resistance of S-MB DATK synthetic surfactant, as well as its promising pulmonary activity in a rabbit model relevant for NRDS and ALI/ARDS
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