Recombinant Human Surfactant Protein D (rhSP-D)

Pulmonary surfactant is a complex mixture of lipids and proteins. The four major surfactant proteins, identified as SP-A, SP-B, SP-C, and SP-D, play important roles in surfactant structure, function and metabolism[1]. SP-D is produced in many organs and in various cell types, although mainly produced and found in the lungs in alveolar type II cells[2]. Surfactant protein D is a member of the collectin family of C-type mammalian lectins The mature form of recombinant human surfactant protein D (rhSP-D) is a 330 residue hydrophilic glycoprotein containing one C-type lectin domain and one collagen-like domain that are connected by a coiled-coil region. (Structural, genetic, and biological information can be found in UniprotKB database entry P35247).

SP-D has a positive influence on the structural form of surfactant and is important in the regulation of alveolar surfactant pool sizes and surfactant recycling by alveolar type II cells[3, 4]. SP-D is also necessary for reducing pulmonary inflammation associated with viral, fungal and bacterial pathogens[5, 6]. SP-D is known to bind bacteria and fungi, aggregate viruses, and promote opsonization and phagocytosis by macrophages[7]. It is also known to be a potent inhibitor of Influenza A virus[8]. SP-D binds to glucoconjugates expressed by a variety of Gram-negative bacteria by way of its lectin domain (carbohydrate recognition domain (CRD)), and is a potent agglutinin of some bacterial strains including Klebsiella pneumoniae, Pseudomonas aeruginosa, Hemophilus influenza, Escherichia coli, and Salmonella Minnesota[9]. The use of a 2.3 mg/kg dose of rhSP-D in combination with 100 mg/kg beractant (Survanta) in the premature newborn lamb model was shown to be more effective in preventing endotoxin shock and in reducing inflammation caused by ventilation over beractant alone[10, 11]. The immune activities of SP-D, combined with data on SP-D-deficient mice, suggest that decreased amounts of SP-D protein in humans may result in clinical disease.

SP-D is not present in any of the currently approved and marketed surfactants (Infasurf, Curosurf, and Survanta). As SP-D is not necessary for survival, this removal was not a concern. Now that the role played by SP-D is better known, it seems reasonable to attempt to reintroduce SP-D into a marketed surfactant preparation to see if it adds any meaningful clinical benefit[5, 12]. Existing data suggest that administration of rhSP-D at a dose of 2 mg/kg in an existing surfactant (approximately 2% of a 100 mg/kg total dose) may be an effective therapy in the prevention of pulmonary problems commonly associated with VLBW premature newborns to maintain normal physiology, as much as possible, including the prevention of BPD[10, 11, 13].

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  1. Perez-Gil, J., Structure of pulmonary surfactant membranes and films: the role of proteins and lipid-protein interactions. Biochim Biophys Acta, 2008. 1778(7-8): p. 1676-95.
  2. Madsen, J., et al., Localization of lung surfactant protein D on mucosal surfaces in human tissues. J Immunol, 2000. 164(11): p. 5866-70.
  3. Ikegami, M., et al., Surfactant protein D influences surfactant ultrastructure and uptake by alveolar type II cells. Am J Physiol Lung Cell Mol Physiol, 2005. 288(3): p. L552-61.
  4. Ikegami, M., et al., Surfactant metabolism in SP-D gene-targeted mice. Am J Physiol Lung Cell Mol Physiol, 2000. 279(3): p. L468-76.
  5. Kingma, P.S. and J.A. Whitsett, In defense of the lung: surfactant protein A and surfactant protein D. Curr Opin Pharmacol, 2006. 6(3): p. 277-83.
  6. Wright, J.R., Immunoregulatory functions of surfactant proteins. Nat Rev Immunol, 2005. 5(1): p. 58-68.
  7. Crouch, E.C., Structure, biologic properties, and expression of surfactant protein D (SP-D). Biochim Biophys Acta, 1998. 1408(2-3): p. 278-89.
  8. Hartshorn, K.L., et al., Evidence for a protective role of pulmonary surfactant protein D (SP-D) against influenza A viruses. J Clin Invest, 1994. 94(1): p. 311-9.
  9. Kuan, S.F., K. Rust, and E. Crouch, Interactions of surfactant protein D with bacterial lipopolysaccharides. Surfactant protein D is an Escherichia coli-binding protein in bronchoalveolar lavage. J Clin Invest, 1992. 90(1): p. 97-106.
  10. Ikegami, M., et al., Intratracheal recombinant surfactant protein d prevents endotoxin shock in the newborn preterm lamb. Am J Respir Crit Care Med, 2006. 173(12): p. 1342-7.
  11. Sato, A., et al., Surfactant protein-d inhibits lung inflammation caused by ventilation in premature newborn lambs. Am J Respir Crit Care Med, 2010. 181(10): p. 1098-105.
  12. Blanco, O. and J. Perez-Gil, Biochemical and pharmacological differences between preparations of exogenous natural surfactant used to treat Respiratory Distress Syndrome: role of the different components in an efficient pulmonary surfactant. Eur J Pharmacol, 2007. 568(1-3): p. 1-15.
  13. Ikegami, M., et al., Surfactant protein-D regulates the postnatal maturation of pulmonary surfactant lipid pool sizes. J Appl Physiol, 2009. 106(5): p. 1545-52.