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

<p>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.</p><p>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.</p><p>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.</p><p>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.</p><h3>List of scientific papers</h3><p>I. Johansson J, Some M, Linderholm BM, Almlén A, Curstedt T, Robertson B (2003). "A synthetic surfactant based on a poly-Leu SP-C analog and phospholipids: effects on tidal volumes and lung gas volumes in ventilated immature newborn rabbits." J Appl Physiol 95(5): 2055-63. Epub 2003 Aug 1 <br><a href="https://pubmed.ncbi.nlm.nih.gov/12897027">https://pubmed.ncbi.nlm.nih.gov/12897027</a><br><br></p><p>II. Almlén A, Stichtenoth G, Robertson B, Johansson J, Curstedt T (2007). "Concentration dependence of a poly-leucine surfactant protein C analogue on in vitro and in vivo surfactant activity." Neonatology 92(3): 194-200. Epub 2007 Apr 27 <br><a href="https://pubmed.ncbi.nlm.nih.gov/17476119">https://pubmed.ncbi.nlm.nih.gov/17476119</a><br><br></p><p>III. Almlén A, Vandenbussche G, Linderholm B, Haegerstrand-Björkman M, Johansson J, Curstedt T (2010). "Alterations of the C-terminal end do not affect in vitro and in vivo activity of SP-C analogues." (Submitted)</p><p>IV. Almlén A, Stichtenoth G, Linderholm B, Haegerstrand-Björkman M, Robertson B, Johansson J, Curstedt T (2008). "Surfactant proteins B and C are both necessary for alveolar stability at end expiration in premature rabbits with respiratory distress syndrome." J Appl Physiol 104(4): 1101-8. Epub 2008 Feb 14 <br><a href="https://pubmed.ncbi.nlm.nih.gov/18276900">https://pubmed.ncbi.nlm.nih.gov/18276900</a><br><br></p><p>V. Almlén A, Walther FJ, Waring AJ, Robertson B, Johansson J, Curstedt T (2010). "Synthetic Surfactant Based on Analogues of SP-B and SP-C Is Superior to Single-Peptide Surfactants in Ventilated Premature Rabbits." Neonatology 98(1): 91-99. [Epub ahead of print] <br><a href="https://pubmed.ncbi.nlm.nih.gov/20110733">https://pubmed.ncbi.nlm.nih.gov/20110733</a><br><br></p>