A recipe for a good clinical pulmonary surfactant

Abstract

The lives of thousands premature babies have been saved along the last thirty years thanks to the establishment and consolidation of pulmonary surfactant replacement therapies (SRT). It took some time to close the gap between the identification of the biophysical and molecular causes of the high mortality associated with respiratory distress syndrome in very premature babies and the development of a proper therapy. Closing the gap required the elucidation of some key questions defining the structure-function relationships in surfactant as well as the particular role of the different molecular components assembled into the surfactant system. On the other hand, the application of SRT as part of treatments targeting other devastating respiratory pathologies, in babies and adults, is depending on further extensive research still required before enough amounts of good humanized clinical surfactants will be available. This review summarizes our current concepts on the compositional and structural determinants defining pulmonary surfactant activity, the principles behind the development of efficient natural animal-derived or recombinant or synthetic therapeutic surfactants, as well as a the most promising lines of research that are already opening new perspectives in the application of tailored surfactant therapies to treat important yet unresolved respiratory pathologies.

Keywords: ARDS; Air–liquid interface; DPPC; Lipid–protein interactions; Respiratory distress syndrome; Surfactant replacement therapy.

Fig. 1

Biogenesis and composition of pulmonary surfactant interfacial films. A) Pulmonary surfactant is assembled and stored by type 2 pneumocytes into special organelles, the Lamellar Bodies (LB). Once the content of LB is secreted by pneumocytes into the alveolar spaces, part of them remain as compact lamellar body-like particles (LBP), while others are converted into tubular myelin (TM), an ordered array of membranes, whose function is still under debate. Ultimately, LBPs and TM transfer surface-active molecules into the air–liquid interface, to form a multilayered surface film competent to stabilize alveoli at the end of expiration. B) Surfactant includes 4 surfactant-associated proteins: the hydrophilic SP-A and SP-D and the hydrophobic, and deeply integrated into lipid, proteins SP-B and SP-C. C) Compositional proportions of different proteins and lipids in a typical pulmonary surfactant.

Fig. 2

Key components of a clinical pulmonary surfactant. The ability of DPPC to pack into highly compact condensed films at the air–liquid interface is the key feature allowing pulmonary surfactant to reduce surface tension to very low values. The coexistence of segregated fluid regions, enriched in unsaturated phospholipids, is important to provide a dynamic character, critical for adsorption and re-spreading of surfactant bilayers along the interface. Hydrophobic surfactant proteins SP-B and SP-C partition into the disordered regions with preferential interaction with the boundaries between ordered and disordered phases. Both proteins require the interaction with the anionic phospholipids PG and PI. SP-B is the key protein to promote transfer of surface-active phospholipids between bilayers and monolayers and to provide maximal mechanical stability at the highest pressures of the films through the establishment of bilayer–monolayer and bilayer–bilayer contacts. SP-C is able to form complexes with SP-B, and participates in monolayer–bilayer transitions from the most fluid domains.