Synthetic pulmonary surfactant : Effects of surfactant proteins B and C and their analogues

Detta är en avhandling från Stockholm : Karolinska Institutet, Department of Molecular Medicine and Surgery

Sammanfattning: Pulmonary surfactant is a lipid/protein mixture lining the air-liquid interface in the alveoli. Its main function is to lower surface tension during respiration and thereby prevent alveolar collapse at end-expiration. Surfactant deficiency, especially common in prematurely born babies, is the main cause of respiratory distress syndrome (RDS). This disease is treated with exogenous surfactant replacement using animal-derived modified natural surfactants. Production of these is quite expensive and the supply is limited. In addition there is a possible risk of transmitted infectious agents, which is why synthetic alternatives are under development. We investigated the effect of an SP-C analogue, SP-C33, in phospholipids as a synthetic alternative. By circular dichroism and infrared spectroscopy we found that SP-C33 shows secondary structure and orientation in a phospholipid bilayer similar to SP-C. 1-2% of this analogue in a mixture of dipalmitoylphosphatidylcholine (DPPC)/palmitoyloleoylphosphatidylglycerol (POPG) (68:31 by weight) showed tidal volumes similar to those obtained by the modified natural surfactant Curosurf when used in ventilated prematurely born rabbits. When ventilated without positive end-expiratory pressure, SP-C33 surfactant shows lower lung gas volumes (LGV) compared to Curosurf, indicating that some component in the latter is needed to stabilize the lung at end-expiration. Our study shows that inclusion of both SP-C33 and SP-B, or an analogue thereof, significantly increases LGV. This indicates that SP-B and SP-C exerts different tasks in surfactant and that both proteins are necessary to obtain alveolar stability. The SP-B analogue Mini-B shows good surfactant activity both in vitro and in vivo and may be a good replacement in synthetic surfactant. C-terminal modifications of SP-C33 do not alter its surfactant properties, indicating that mobility inside the membrane probably is not necessary for surfactant activity. A synthetic surfactant consisting of 2% SP-C33 (by weight) in 80mg/ml DPPC/POPG (68:31 w/w) and an SP-B analogue, possibly Mini-B, may be a good replacement for modified natural surfactant in future treatment of neonatal RDS.

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