Alternative titles; symbols
HGNC Approved Gene Symbol: SFTPD
Cytogenetic location: 10q22.3 Genomic coordinates (GRCh38) : 10:79,937,740-79,982,383 (from NCBI)
Pulmonary surfactant consists of a complex mixture of phospholipids and several proteins essential to normal respiratory function. Surfactant proteins SP-B (SFTP3; 178640) and SP-C (SFTP2; 178620) and the surfactant lipids are involved in the reduction of surface tension at the air-liquid barrier in the alveoli of the lung, whereas the surfactant protein SP-A (SFTPA1; 178630) and SP-D appear to contribute to local immune defense by mediating phagocytosis. SP-D was identified in lung lavage by its similarity to rat SP-D in both its molecular mass and its Ca(2+)-dependent-binding affinity for maltose. A high concentration of glycine (22%), hydroxyproline, and hydroxylysine in the amino acid composition of SP-D indicated that it contained a collagen-like structure. Collagenase digestion yielded a 20-kD collagenase-resistant globular fragment that retained affinity for maltose.
Rust et al. (1991) isolated cDNA clones for human SP-D and derived the complete amino acid sequence. By screening a human lung cDNA library with oligonucleotide probes, Lu et al. (1992) isolated 2 cDNA clones that overlapped to give the full coding sequence of SP-D. The derived amino acid sequence indicated that the mature polypeptide chain has 355 amino acid residues with a short noncollagen-like N-terminal section of 25 residues, followed by a collagen-like region of 177 residues and a C-terminal C-type lectin domain of 153 residues. SP-A and SP-D show an overall structural similarity since both contain a collagen-like domain composed of multiple gly-X-Y repeats and a carboxy-terminal, C-type carbohydrate recognition domain.
SP-D, SP-A, and mannose-binding lectin (MBL; 154545) are collectins, members of the C-type lectin family. The collectins are composed of 4 domains: a short amino-terminal region with interchain disulfide bonds, a long collagen-like domain, a coiled-coil neck region, and a calcium-dependent carbohydrate recognition domain. The basic structural unit of each collectin is a trimer based on the collagen-like triple helix, but the arrangement of multiple trimers into higher order oligomers varies. Kolble et al. (1993) used the CLUSTAL V computer program to calculate the evolutionary relationships of MBL and the surfactant genes.
On the basis of homology with other collectins, potential functions for SP-D include roles in innate immunity and surfactant metabolism (Botas et al., 1998).
Holmskov et al. (1997) identified GP340 (DMBT1; 601969) by its calcium-dependent binding to SFTPD. They presented findings indicating that the binding between GP340 and SFTPD is a protein-protein interaction rather than a lectin-carbohydrate interaction and that the binding to GP340 takes place via the carbohydrate recognition domain of SFTPD. Holmskov et al. (1997) concluded that GP340 is likely to be a truncated form of a receptor for SFTPD. Holmskov et al. (1999) found that GP340 exists both in a soluble form and in association with the membranes of alveolar macrophages. The distribution of GP340 in macrophages was found to be compatible with a role as an opsonin receptor for SFTPD. Holmskov et al. (1999) concluded that the molecular interaction between SFTPD and GP340 probably plays an important role in innate immunity on mucosal surfaces.
Mori et al. (2002) found immunohistochemical evidence that SP-D is produced in the bronchiolar and terminal epithelium of human fetal lung from about 21 weeks of gestation.
Gardai et al. (2003) found that the collectins SPA and SPD helped maintain a noninflammatory environment in lung by stimulating the immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing SIRPA (PTPNS1; 602461) on resident alveolar cells through their globular head, C-lectin domains. However, when these domains interacted with pathogen-associated molecular patterns (PAMP) on foreign organisms, apoptotic cells, or cell debris, presentation of the collectins' collagenous tails in an aggregated state to CALR (109091)/CD91 (LRP1; 107770) on the alveolar cells initiated ingestion and generation of proinflammatory and proimmunogenic responses. Gardai et al. (2003) proposed that SPA and SPD act as dual-function surveillance molecules that reverse orientation and function and become initiators of host-defense reactions.
Barrow et al. (2015) used a bioinformatics approach to identify collagenous molecules with immunologic roles that contain a putative OSCAR (606862)-binding motif. The authors thus identified the collagenous domain of SPD and showed that it was a specific, calcium-enhanced binding partner of OSCAR. Full-length SPD in bronchoalveolar lavage fluid also bound OSCAR. Immunofluorescence microscopy demonstrated that SPD-containing alveolar macrophages bound OSCAR in intracellular compartments, whereas OSCAR was predominantly expressed on the surface of interstitial lung and blood CCR2 (601267)-positive inflammatory monocytes. Following stimulation with SPD, these monocytes secreted TNF (191160). OSCAR and SPD were also highly expressed in atherosclerotic plaques in aorta. Barrow et al. (2015) proposed that OSCAR/SPD interaction may be a target in chronic lung inflammatory diseases.
Crouch et al. (1993) partially characterized genomic clones for SFTP4 and found that the gene has coding sequences spanning more than 11 kb.
By fluorescence in situ hybridization, Crouch et al. (1993) localized the SFTP4 gene in 10q22.2-q23.1. Kolble et al. (1993) used PCR-based somatic cell hybrid mapping to assign the SFTP4 gene to chromosome 10. A regional mapping panel was used to place SFTP4 in the interval 10q22-q23. Low-stringency PCR using the SFTP1 primer pair suggested the presence of at least 2 additional SFTP1-related genes in the same region. With the locus for MBL at 10q21, the findings may indicate this region's central role in the evolutionary history of carbohydrate-binding proteins containing collagen-like regions.
The close linkage of mouse collectin genes on chromosome 14 of that species suggests that the collectins arose by ancestral gene duplication.
By analysis of same-sex monozygotic and dizygotic twins aged 6 to 9 years, Husby et al. (2002) estimated the heritability of serum concentrations of the collectins SPD and MBL to be 0.91 and 0.96, respectively. The data indicated that there is a strong genetic, rather than environmental, dependence for serum levels of SPD and MBL.
Botas et al. (1998) disrupted the SP-D gene in mouse embryonic stem cells by homologous recombination to generate mice deficient in SP-D. Heterozygous mice had SP-D concentrations that were approximately 50% wildtype but no other obvious phenotypic abnormality. Mice totally deficient in SP-D were healthy to 7 months but had a progressive accumulation of surfactant lipids, SP-A, and SP-B in the alveolar space. By 8 weeks, the alveolar phospholipid pool was 8-fold higher than in wildtype littermates. There was also a 10-fold accumulation of alveolar macrophages in the null mice, and many macrophages were both multinucleated and foamy in appearance. Type II cells in the null mice were hyperplastic and contained giant lamellar bodies. These alterations in surfactant homeostasis were not associated with detectable changes in surfactant surface activity, postnatal respiratory function, or survival. The findings in the SP-D deficient mice suggested a role for SP-D in surfactant homeostasis.
Wert et al. (2000) described the progressive development of pulmonary emphysema and subpleural fibrosis, associated with chronic inflammation and increased matrix metalloproteinase (e.g., MMP9; 120361) activity and oxidant production by alveolar macrophages, in mice rendered SP-D -/- by targeted gene inactivation.
LeVine et al. (2001) infected wildtype and Spd -/- mice intranasally with influenza A virus (IAV). Spd concentration increased in wildtype mice. Spd-deficient mice showed decreased viral clearance and increased production of inflammatory cytokines. Phagocytosis by alveolar macrophages was comparable in both groups of mice, but higher numbers of neutrophils with low myeloperoxidase (MPO; 606989) activity accumulated in the lungs of Spd-deficient mice. Using a less-glycosylated strain of IAV, the authors found that viral clearance was unaffected by Spd deficiency. Viral clearance of the more glycosylated strain could be normalized by coadministration of recombinant Spd to the Spd -/- mice. LeVine et al. (2001) proposed that SPD probably plays an important role in innate defense responses to influenza A virus and other respiratory pathogens.
Zhang et al. (2002) introduced a chimeric cDNA encoding the N terminus and collagen domain of rat Spd and the neck and carbohydrate recognition domain (CRD) of a bovine collectin, conglutinin, into Spd-null mice. Expression of the fusion protein substantially reversed the lung phospholipid accumulation, defects in influenza A clearance, and exaggerated inflammatory response following viral infection associated with Spd deficiency. However, the chimeric protein did not ameliorate the ongoing lung inflammation, enhanced metalloproteinase expression, or development of emphysema. Zhang et al. (2002) concluded that the CRDs of both SPD and conglutinin have general roles in host defense in vivo, but the neck and CRD domains of SPD are specifically required to regulate oxidant injury and lung remodeling.
Barrow, A. D., Palarasah, Y., Bugatti, M., Holehouse, A. S., Byers, D. E., Holtzman, M. J., Vermi, W., Skjodt, K., Crouch, E., Colonna, M. OSCAR is a receptor for surfactant protein D that activates TNF-alpha release from human CCR2+ inflammatory monocytes. J. Immun. 194: 3317-3326, 2015. [PubMed: 25716998] [Full Text: https://doi.org/10.4049/jimmunol.1402289]
Botas, C., Poulain, F., Akiyama, J., Brown, C., Allen, L., Goerke, J., Clements, J., Carlson, E., Gillespie, A. M., Epstein, C., Hawgood, S. Altered surfactant homeostasis and alveolar type II cell morphology in mice lacking surfactant protein D. Proc. Nat. Acad. Sci. 95: 11869-11874, 1998. [PubMed: 9751757] [Full Text: https://doi.org/10.1073/pnas.95.20.11869]
Crouch, E., Rust, K., Veile, R., Donis-Keller, H., Grosso, L. Genomic organization of human surfactant protein D (SP-D): SP-D is encoded on chromosome 10q22.2-23.1. J. Biol. Chem. 268: 2976-2983, 1993. [PubMed: 8428971]
Gardai, S. J., Xiao, Y.-Q., Dickinson, M., Nick, J. A., Voelker, D. R., Greene, K. E., Henson, P. M. By binding SIRP-alpha or calreticulin/CD91, lung collectins act as dual function surveillance molecules to suppress or enhance inflammation. Cell 115: 13-23, 2003. [PubMed: 14531999] [Full Text: https://doi.org/10.1016/s0092-8674(03)00758-x]
Holmskov, U., Lawson, P., Teisner, B., Tornoe, I., Willis, A. C., Morgan, C., Koch, C., Reid, K. B. M. Isolation and characterization of a new member of the scavenger receptor superfamily, glycoprotein-340 (gp-340), as a lung surfactant protein-D binding molecule. J. Biol. Chem. 272: 13743-13749, 1997. [PubMed: 9153228] [Full Text: https://doi.org/10.1074/jbc.272.21.13743]
Holmskov, U., Mollenhauer, J., Madsen, J., Vitved, L., Gronlund, J., Tornoe, I., Kliem, A., Reid, K. B. M., Poustka, A., Skjodt, K. Cloning of gp-340, a putative opsonin receptor for lung surfactant protein D. Proc. Nat. Acad. Sci. 96: 10794-10799, 1999. [PubMed: 10485905] [Full Text: https://doi.org/10.1073/pnas.96.19.10794]
Husby, S., Herskind, A. M., Jensenius, J. C., Holmskov, U. Heritability estimates for the constitutional levels of the collectins mannan-binding lectin and lung surfactant protein D. A study of unselected like-sexed mono- and dizygotic twins at the age of 6-9 years. Immunology 106: 389-394, 2002. [PubMed: 12100727] [Full Text: https://doi.org/10.1046/j.1365-2567.2002.01436.x]
Kolble, K., Lu, J., Mole, S. E., Kaluz, S., Reid, K. B. M. Assignment of the human pulmonary surfactant protein D gene (SFTP4) to 10q22-q23 close to the surfactant protein A gene cluster. Genomics 17: 294-298, 1993. [PubMed: 8406480] [Full Text: https://doi.org/10.1006/geno.1993.1324]
LeVine, A. M., Whitsett, J. A., Hartshorn, K. L., Crouch, E. C., Korfhagen, T. R. Surfactant protein D enhances clearance of influenza A virus from the lung in vivo. J. Immun. 167: 5868-5873, 2001. [PubMed: 11698462] [Full Text: https://doi.org/10.4049/jimmunol.167.10.5868]
Lu, J., Willis, A. C., Reid, K. B. M. Purification, characterization and cDNA cloning of human lung surfactant protein D. Biochem. J. 284: 795-802, 1992. [PubMed: 1339284] [Full Text: https://doi.org/10.1042/bj2840795]
Mori, K., Kurihara, N., Hayashida, S., Tanaka, M., Ikeda, K. The intrauterine expression of surfactant protein D in the terminal airways of human fetuses compared with surfactant protein A. Europ. J. Pediat. 161: 431-434, 2002. [PubMed: 12172826] [Full Text: https://doi.org/10.1007/s00431-002-0917-9]
Rust, K., Grosso, L., Zhang, V., Chang, D., Persson, A., Longmore, W., Cai, G.-Z., Crouch, E. Human surfactant protein D: SP-D contains a C-type lectin carbohydrate recognition domain. Arch. Biochem. Biophys. 290: 116-126, 1991. [PubMed: 1898081] [Full Text: https://doi.org/10.1016/0003-9861(91)90597-c]
Wert, S. E., Yoshida, M., LeVine, A. M., Ikegami, M., Jones, T., Ross, G. F., Fisher, J. H., Korfhagen, T. R., Whitsett, J. A. Increased metalloproteinase activity, oxidant production, and emphysema in surfactant protein D gene-inactivated mice. Proc. Nat. Acad. Sci. 97: 5972-5977, 2000. [PubMed: 10801980] [Full Text: https://doi.org/10.1073/pnas.100448997]
Zhang, L., Hartshorn, K. L., Crouch, E. C., Ikegami, M., Whitsett, J. A. Complementation of pulmonary abnormalities in SP-D(-/-) mice with an SP-D/conglutinin fusion protein. J. Biol. Chem. 277: 22453-22459, 2002. [PubMed: 11956209] [Full Text: https://doi.org/10.1074/jbc.M201632200]