Synthetic pulmonary surfactant : effects of surfactant proteins B and C and their analogues
Author: Almlén, Andreas
Date: 2010-09-09
Location: Thoraxaulan, N2:U1, Karolinska Universitetssjukhuset, Solna
Time: 09.00
Department: Institutionen för molekylär medicin och kirurgi / Department of Molecular Medicine and Surgery
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thesis.pdf (1.644Mb)
Abstract
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.
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.
List of papers:
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
Pubmed
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
Pubmed
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)
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
Pubmed
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]
Pubmed
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
Pubmed
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
Pubmed
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)
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
Pubmed
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]
Pubmed
Issue date: 2010-08-19
Rights:
Publication year: 2010
ISBN: 978-91-7409-966-9
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