New synthetic surfactants--basic science.

The hydrophobic surfactant proteins, SP-B and SP-C, promote adsorption of surface-active lipids to the air-liquid interface of the alveoli and are essential for alveolar stability and gas exchange. Synthetic surfactant preparations must contain at least one of these hydrophobic proteins, or analogs thereof, to have optimal effects when administered into the airways of patients with lung diseases. However, development of clinically active artificial surfactants has turned out to be more complicated than initially anticipated since the native hydrophobic proteins are structurally complex or unstable in pure form. The proteins have been replaced by different analogs which have the right conformation without forming oligomers. Increased understanding of the surfactant proteins will hopefully lead to development of effective synthetic surfactants which can be produced in large quantities for treatment of a wide range of respiratory disorders. Furthermore, the lipid composition seems to be important, as well as a high lipid concentration in the suspension. For successful treatment of many respiratory diseases, it is also desirable that the synthetic surfactant resists inactivation by plasma components leaking into the alveoli.

New synthetic surfactants: the next generation?

Surfactant preparations have been proven to improve clinical outcome of infants at risk for or having respiratory distress syndrome (RDS). In clinical trials, ani mal-derived surfactant preparations reduce the risk of pneumothorax and mortality when compared to non-protein-containing synthetic surfactant preparations. In part, this is thought to be due to the presence of surfactant proteins in animal-derived surfactant preparations. Four native surfactant proteins have been identified. The hydrophobic surfactant proteins B (SP-B) and C (SP-C) are tightly bound to phospholipids. These proteins have important roles in maintaining the surface tension-lowering properties of pulmonary surfactant. Surfactant protein A (SP-A) and D (SP-D) are extremely hydrophilic and are not retained in the preparation of any commercial animal-derived surfactant products. These proteins are thought to have a role in recycling surfactant and improving host defense. There is concern that animal-derived products may have some batch-to-batch variation regarding the levels of native pulmonary surfactant proteins. In addition, there is concern regarding the hypothetical risk of transmission of viral or unconventional infectious agents from an animal source. New surfactant preparations, composed of synthetic phospholipids and essential hydrophobic surfactant protein analogs, have been developed. These surfactant protein analogs have been produced by peptide synthesis and recombinant technology to provide a new class of synthetic surfactants that may be a suitable alternative to animal-derived surfactants. Preliminary clinical studies have shown that treatment with these novel surfactant preparations can ameliorate RDS and improve clinical outcome. Clinicians will need to further understand any differences in clinical effects between available products.

Simple, helical peptoid analogs of lung surfactant protein B.

The helical, amphipathic surfactant protein, SP-B, is a critical element of pulmonary surfactant and hence is an important therapeutic molecule. However, it is difficult to isolate from natural sources in high purity. We have created and studied three different, nonnatural analogs of a bioactive SP-B fragment (SP-B(1-25)), using oligo-N-substituted glycines (peptoids) with simple, repetitive sequences designed to favor the formation of amphiphilic helices. For comparison, a peptide with a similar repetitive sequence previously shown to be a good SP mimic was also studied, along with SP-B(1-25) itself. Surface pressure-area isotherms, surfactant film phase morphology, and dynamic adsorption behavior all indicate that the peptoids are promising mimics of SP-B(1-25). The extent of biomimicry appears to correlate with peptoid helicity and lipophilicity. These biostable oligomers could serve in a synthetic surfactant replacement to treat respiratory distress syndrome.

Surfactant with SP-B and SP-C analogues improves lung function in surfactant-deficient rats.

The use of mammalian lung surfactant extracts has sharply reduced mortality and morbidity from respiratory distress syndrome in premature infants. Synthesis of surfactant protein B and C (SP-B and SP-C) analogues may lead the way to a synthetic surfactant preparation. Dimeric SP-B(1-25) (dSP-B(1-25)) is based on the N-terminal domain of human SP-B and SP-Cfc is a modified human SP-C in which a single phenylalanine is substituted for a palmitoylated cysteine residue in the N-terminal segment (Phe-4 > Cys-4 variant). We tested the effects of synthetic surfactants with 1 or 2% dSP-B(1-25) and 1% SP-Cfc on lung function in surfactant-deficient rats. Four experimental surfactant preparations were prepared by mixing 1% dSP-B(1-25), 2% dSP-B(1-25), 1% dSP-B(1-25) +1% SP-Cfc, and 2% dSP-B(1-25) +1% SP-Cfc with phospholipids (PL). PL and Survanta, a bovine lung extract, were controls. Groups of 8 rats were ventilated, lavaged until surfactant deficiency, and treated with 100 mg/kg surfactant. Arterial blood gas values and dynamic compliance were measured every 15 min and after 2 h of ventilation, the rats were killed and pressure-volume curves performed. Oxygenation improved quickly after instillation of surfactant with synthetic peptides and Survanta. Oxygenation and lung volumes were consistently higher in the 2% than in the 1% dSP-B(1-25) groups. Addition of 1% SP-Cfc to the synthetic surfactants further improved oxygenation and lung volume, but to a lesser extent than increasing the dSP-B(1-25) content from 1 to 2%. These data indicate that improvements in oxygenation and lung volume in lavaged rats are dependent on the concentration of dSP-B(1-25) in the surfactant preparation and that the presence of SP-Cfc has a relative minor effect on these parameters.