New avenues in surfactant research

Treatment with exogenous surfactant improves lung function and survival in babies with respiratory distress syndrome (RDS) and is now part of routine clinical management of this disease. There is still some controversy as to the dose requirements and timing of therapy in premature babies needing exogenous surfactant, but most authors agree that the initial dose should be close to the estimated pool size of alveolar surfactant in a normal fullterm newborn baby, about 100 mg/kg [8]. Not surprisingly, the clinical response further depends on the quality of the exogenous material, modified natural surfactants containing the native hydrophobic poly-peptides SP-B and SP-C being more effective than protein-free synthetic surfactants [4]. In a recent randomised clinical trial comparing modified porcine surfactant (poractant alfa, Curosurf®, Chiesi Farmaceutici, Parma, Italy) with a protein-free synthetic product (pumactant, ALEC®, Britannia Pharmaceuticals, Redhill, Surrey, UK) for prophylaxis of RDS, the outcome was much better in babies receiving the porcine surfactant (mortality: 14 vs. 31 %, P < 0.01) [1].

Surfactant therapy might be helpful also in various forms of lung disease, in which endogenous surfactant is inactivated by aspirated material and/or leakage of plasma proteins to the airspaces. Meconium contains several components that may interfere with surfactant function, such as cholesterol, free fatty acids, and bilirubin, and aspiration of these substances may cause an immediate fall in lung compliance. Aspirated meconium also obstructs conducting airways and induces an inflammatory response with recruitment of granulocytes, permeation of plasma proteins to the airspaces, and formation of hyaline membranes. Exogenous surfactant may counterbalance these pathophysiological events, but relatively large amounts of surfactant are usually required. In a recent randomised clinical trial on babies with severe respiratory failure from meconium aspiration, treatment with beractant (Survanta®, Abbott, North Chicago, IL) effectively improved gas exchange, but three doses of surfactant (each 150 mg/kg) at 6-h intervals were required for maximal response [2].

Surfactant therapy also improves lung function in experimental [7] and clinical [6] neonatal group B streptococcal (GBS) pneumonia, but the improvement in gas exchange is less dramatic than in babies with RDS receiving surfactant. Some babies with GBS pneumonia probably have an element of primary surfactant deficiency, whereas others have adequate pools of surfactant to start with but their endogenous supply gradually becomes inactivated by the inflammatory exsudate. Again, comparatively large doses of surfactant may be required for a satisfactory clinical response. Interaction with bacteria varies according to the type of surfactant as well as the type of microorganism involved. For example, poractant alfa (but not beractant) has a bacteriostatic effect when added to GBS cultured in nutrient-free medium, whereas beractant (but not poractant alfa) stimulates growth of Escherichia coli cultured under similar conditions [11]. The bacteriostatic effect of poractant alfa may be related to the presence of a granulocyte derived antibacterial peptide, prophenin, which coisolates with the surfactant lipids and hydrophobic proteins in porcine surfactant [16]. Bacterial growth can be further prevented in newborn rabbits with experimental pneumonia by adding specific antibacterial antibodies to the exogenous surfactant [3] [5]. It has been proposed that surfactant may serve as a “carrier” for the antibody, but the exact mechanism involved in this cooperative process remains to be clarified.

Preventing surfactant inactivation is an important new approach that could increase the therapeutic effect of exogenous surfactant in meconium aspiration syndrome and other forms of inflammatory lung disease. Sensitivity to inactivation varies between different surfactants and is in part related to their protein content [12]. Recent in vitro studies with pulsating bubble have revealed that modified natural surfactants such as beractant, poractant alfa and SF-RI 1 (Alveofact®, Thomae, GmbH, Biberach, Germany) are quite sensitive to inactivation by meconium, as reflected by a significant increase in minimum surface tension at a meconium:surfactant concentration ratio as low as 0.016. Complete natural surfactant containing both hydrophobic and hydrophilic components including the water-soluble proteins SP-A and SP-D, is much more resistant to inactivation, and does not show an increase in minimum surface tension until the meconium : surfactant concentration ratio is raised > 4. Two recently developed artificial surfactants based on KL₄ (a synthetic peptide allegedly serving as an analogue of SP-B) or recombinant SP-C were also tested in the same in vitro system and showed an intermediate sensitivity to inactivation by meconium [13]. Interestingly, the resistance to inactivation of a surfactant preparation can be enhanced by addition of non-ionic polymers (dextran, polyethylene glycol). The protective effect of such polymers added to surfactant is reflected in the restoration of low minimum surface tension during cyclic film compression despite presence of meconium [9] [10] [ 14] [15] and further improvement of gas exchange and lung compliance in animals with experimental meconium aspiration syndrome receiving surfactant [10]. Molecular mechanisms involved in the interaction between non-ionic polymers and surfactant are not well understood, but could be related to a phenomenon known as “macromolecular crowding”, i.e. to binding of water by the polymers, leading to increased concentration of surfactant molecules available for adsorption at the air-liquid interface [14]. It seems likely that ongoing research on structure-function relationships of surfactant proteins will lead to the development of a new generation of artificial surfactant substitutes based on synthetic analogues of SP-B and/or SP-C. These surfactant preparations can probably be tailored to optimize therapeutic effects in various forms of lung disease, for example by maximizing bacteriostatic effects and resistance to inactivation. Clinical trials of new artificial surfactants, based on KL₄ or recombinant SP-C, for treatment of neonatal and adult RDS are currently in progress.

Literatur

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