Affinage

SFTPD

Pulmonary surfactant-associated protein D · UniProt P35247

Length
375 aa
Mass
37.7 kDa
Annotated
2026-06-10
100 papers in source corpus 31 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SP-D (SFTPD) is a secreted collagenous C-type lectin synthesized by type II pneumocytes and Clara cells that serves dual roles in innate pulmonary immunity and alveolar surfactant homeostasis (PMID:2675969, PMID:1527377). Each polypeptide combines an N-terminal collagenous region of uninterrupted Gly-X-Y triplets with a C-type lectin carbohydrate recognition domain (CRD) that binds saccharides in a calcium-dependent manner (PMID:1898081); trimers assemble through interchain disulfide bonds in the N-terminal domain into cruciform dodecamers and higher-order multimers, an architecture that determines functional valency (PMID:8006040, PMID:29626540). Through its CRD the protein binds endogenous surfactant lipids—phosphatidylinositol and glucosylceramide—as well as microbial surfaces, neutralizing influenza A virus by aggregation and potentiating neutrophil antiviral responses, with multimerization markedly enhancing potency (PMID:1457414, PMID:1530650, PMID:8040272, PMID:8944718). The CRD also confers direct chemoattractant activity toward neutrophils and monocytes via saccharide-recognizing cell-surface sites (PMID:7695920, PMID:9887065) and engages the membrane-proximal D3 domain of SIRPα/SIRPβ to modulate innate immune cell signaling (PMID:22511785). SP-D restrains injurious neutrophil and eosinophil extracellular trap formation by binding LPS and cell membranes, thereby protecting surfactant biophysical function (PMID:31872075, PMID:29733456). In vivo, disulfide-crosslinked oligomers are required for regulation of surfactant phospholipid pools and prevention of emphysema and foamy-macrophage accumulation; loss of SP-D causes lipid accumulation, persistent lung T-cell activation, and airspace remodeling (PMID:10956621, PMID:11278637, PMID:12091242), and the antimicrobial CRD function is mechanistically separable from collagen-domain-dependent lipid homeostasis and emphysema prevention (PMID:11956209, PMID:16787926). Transcription of Sftpd is driven by a calcineurin/NFATc3–TTF-1 complex (PMID:15173172), while MMP-9 cleavage or S-nitrosylation-induced de-oligomerization abolishes its immune functions (PMID:22860023, PMID:29733456).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1989 High

    Establishing that SP-D is a collagenous glycoprotein assembling from disulfide-bonded trimers defined the protein class and quaternary basis for all later function.

    Evidence HPLC purification, microsequencing, and electrophoresis of rat BAL protein

    PMID:2675969

    Open questions at the time
    • Higher-order assembly geometry not yet defined
    • No ligand or functional activity yet assigned
  2. 1991 High

    Cloning revealed a calcium-dependent C-type lectin CRD joined to a collagenous N-terminal domain, explaining how a collagenous protein could function as a sugar-recognizing molecule.

    Evidence cDNA library screening, sequencing, and peptide microsequencing of human SP-D

    PMID:1898081

    Open questions at the time
    • Physiological saccharide ligands not identified
    • CRD residues mediating specificity unknown
  3. 1992 High

    Identifying phosphatidylinositol and glucosylceramide as calcium-dependent CRD ligands showed SP-D recognizes endogenous surfactant lipids, not only microbial sugars, and defined its localization across pulmonary cell compartments.

    Evidence TLC overlay binding with radioiodinated SP-D, MS lipid identification, immunogold EM

    PMID:1457414 PMID:1527377 PMID:1530650

    Open questions at the time
    • Functional consequence of lipid binding unresolved
    • Structural basis of lipid versus sugar recognition unknown
  4. 1994 High

    Defining the dodecameric four-armed architecture and demonstrating potent influenza A neutralization linked quaternary structure to CRD-mediated antiviral defense.

    Evidence Electron microscopy, pepsin/collagenase digestion, hemagglutination inhibition and neutrophil assays

    PMID:8006040 PMID:8040272

    Open questions at the time
    • Receptor mediating neutrophil effects not identified
    • Quantitative valency-potency relationship not yet established
  5. 1995 High

    Showing SP-D is a CRD-dependent chemoattractant for neutrophils and monocytes extended its role from pathogen aggregation to active recruitment of immune cells.

    Evidence Boyden chamber chemotaxis with sugar competition and antibody blocking

    PMID:7695920

    Open questions at the time
    • Cell-surface receptor for chemotaxis not identified
    • Signaling pathway downstream unknown
  6. 1996 High

    Demonstrating that multimers of dodecamers exceed dodecamers in antiviral potency established CRD valency as a tunable determinant of function encoded in primary structure.

    Evidence Recombinant SP-D oligomer fractionation, EM, and antiviral assays

    PMID:8944718

    Open questions at the time
    • Molecular driver of higher-order multimerization not pinpointed
  7. 1999 High

    Showing the isolated trimeric CRD suffices for chemotaxis localized the chemoattractant function to the lectin domain independent of the collagenous stalk.

    Evidence Recombinant CRD expression and Boyden chamber assay with sugar competition

    PMID:9887065

    Open questions at the time
    • Receptor still unidentified
    • Single-lab in vitro result
  8. 2000 High

    Knockout and lung-specific rescue established that SP-D regulates alveolar surfactant phospholipid homeostasis acting locally within the lung.

    Evidence Sftpd-/- mice and SP-C-promoter transgenic rescue with radiolabeled lipid clearance

    PMID:10666121 PMID:10956621

    Open questions at the time
    • Mechanism linking SP-D to lipid clearance unresolved
    • Cellular target of lipid regulation unclear
  9. 2001 High

    Domain and epistasis genetics showed disulfide-crosslinked oligomers are required in vivo to prevent emphysema and that SP-D and GM-CSF act through distinct additive pathways.

    Evidence Cys→Ser mutant transgenics, SP-D/GM-CSF double-null mice, BAL lipid and histology

    PMID:11278637 PMID:11504698 PMID:1930130

    Open questions at the time
    • Molecular pathway from de-oligomerization to emphysema unknown
    • How SP-D competes with SP-A at type II cell binding sites mechanistically unresolved
  10. 2002 High

    Conditional, chimeric, and domain-swap rescue experiments demonstrated that CRD-mediated antimicrobial defense and collagen/N-terminal-dependent lipid homeostasis and emphysema prevention are mechanistically dissociable functions, and that SP-D suppresses local T-cell activation.

    Evidence Doxycycline-inducible and SP-D/conglutinin CRD chimera transgenics, M. pneumoniae binding with CRD mutagenesis, Sftpd-/- immunophenotyping

    PMID:11916969 PMID:11956209 PMID:12091242 PMID:12163500

    Open questions at the time
    • Why established emphysema is irreversible unknown
    • Mechanism of T-cell suppression undefined
  11. 2004 High

    Identifying the calcineurin/NFATc3–TTF-1 complex on the Sftpd promoter defined the transcriptional control of SP-D expression.

    Evidence Promoter reporter assays, DNase I footprinting, co-IP and in vitro interaction of NFATc3 and TTF-1

    PMID:15173172

    Open questions at the time
    • Upstream signals activating calcineurin in vivo unclear
    • Additional regulatory inputs not mapped
  12. 2005 High

    Linking a Met11Thr polymorphism to defective multimerization tied SP-D oligomeric state to ligand selectivity, with multimers favoring intact pathogens and monomers favoring isolated LPS.

    Evidence SFTPD genotyping, AFM, recombinant protein, and solid-phase binding assays

    PMID:15661913

    Open questions at the time
    • Functional clinical consequence of polymorphism not established in this corpus
  13. 2006 High

    Domain-deletion, chimeric, and structural studies dissected collagen-domain-dependent macrophage/airspace regulation from CRD function, identified Phe-335 as the aromatic ring-stacking residue for extended saccharides, and revealed a systemic role of SP-D in lipid/energy homeostasis.

    Evidence Collagen-deletion and SP-A/SP-D chimera transgenics, CRD crystallography with mutagenesis, Sftpd-/- body weight and human BMI cohort

    PMID:16500946 PMID:16636058 PMID:16787926 PMID:17083619

    Open questions at the time
    • Mechanism connecting SP-D to systemic fat regulation undefined
    • How collagen domain controls macrophage activation unknown
  14. 2009 High

    Identifying the SIRPα/β D3 binding site and distinct oligomer-dependent ligand profiles refined how SP-D signals to immune cells and how its assembly state selects targets.

    Evidence SIRP domain-deletion and N-glycosylation mutagenesis, binding assays, trimer/multimer fractionation

    PMID:19577304 PMID:22511785

    Open questions at the time
    • Downstream SIRP signaling consequences not defined
    • Trimer/multimer interconversion in vivo unclear
  15. 2012 Medium

    Showing MMP-9 cleavage abolishes bacterial aggregation and phagocytosis while sparing LPS binding established proteolytic inactivation as a regulatory and pathological mechanism with site-specific functional outcomes.

    Evidence In vitro MMP-9 and neutrophil elastase cleavage with functional readouts

    PMID:22860023

    Open questions at the time
    • In vivo relevance of cleavage not established
    • Cleavage sites not mapped at residue resolution
  16. 2019 High

    Demonstrating that SP-D binds LPS and cell membranes to suppress neutrophil and eosinophil extracellular trap formation, and that S-nitrosylation-induced de-oligomerization abolishes this, connected SP-D oligomeric integrity to protection of surfactant biophysical function.

    Evidence NETosis/EET assays, Sftpd-/- LPS lung models, in vitro S-nitrosylation, surfactant function assays

    PMID:29733456 PMID:31872075

    Open questions at the time
    • Receptor/membrane determinants of trap suppression unresolved
    • In vivo extent of S-nitrosylation regulation under disease unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • The cell-surface receptors mediating SP-D chemotaxis and immune-cell signaling, and the molecular pathway linking SP-D oligomeric state to emphysema and systemic lipid homeostasis, remain undefined.
  • No identified receptor for chemoattractant activity
  • Mechanistic link from de-oligomerization to airspace remodeling unknown
  • Pathway connecting SP-D to systemic energy homeostasis uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0005198 structural molecule activity 3 GO:0008289 lipid binding 3
Localization
GO:0005576 extracellular region 2 GO:0005783 endoplasmic reticulum 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-168256 Immune System 5 R-HSA-1430728 Metabolism 4 R-HSA-74160 Gene expression (Transcription) 1
Partners
SFTPA1SIRPASIRPB1

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1989 SP-D (CP4) was purified from rat bronchoalveolar lavage and characterized as a collagenous glycoprotein (43 kDa reduced) synthesized by type II pulmonary epithelial cells, containing 4-hydroxyproline, hydroxylysine, and collagenous Gly-X-Y triplet sequences; it assembles via disulfide-bonded trimers into high-molecular-mass complexes. Reverse-phase HPLC purification, amino acid analysis, gas-phase N-terminal microsequencing, two-dimensional IEF/SDS-PAGE, gel filtration Biochemistry High 2675969
1991 Human SP-D contains a C-type lectin carbohydrate recognition domain (CRD) with calcium-dependent saccharide binding; the CRD is highly homologous to mannose-binding subfamily C-type lectins and contains four conserved cysteine residues; the N-terminal domain encodes a collagenous region with 59 uninterrupted Gly-X-Y triplets and a single N-linked glycosylation consensus site. cDNA library screening with degenerate oligonucleotide probe, DNA sequencing, N-terminal microsequencing of peptides, immunoprecipitation of translation products Archives of biochemistry and biophysics High 1898081
1992 SP-D binds glucosylceramide (GlcCer) exclusively among a panel of glycolipids tested, in a calcium-dependent manner requiring Ca2+ (not Mg2+); this binding occurs via the lectin domain as shown by antibody inhibition and competitive displacement. TLC overlay binding with 125I-labeled SP-D, competitive inhibition assays, antibody blocking Biochemical and biophysical research communications Medium 1530650
1992 The major glycolipid ligand of SP-D in lung surfactant is phosphatidylinositol (PI); SP-D binds PI in a calcium-dependent, saccharide-inhibitable manner and can recognize PI presented in lipid bilayers (liposomes). 2D-TLC overlay with radioiodinated SP-D, lipid purification and mass spectrometry identification, Percoll density gradient with liposomes Biochemistry High 1457414
1992 SP-D is localized in type II cells (endoplasmic reticulum predominantly), Clara cells (secretory granules at cell periphery distinct from lamellar bodies), and alveolar macrophages (endocytotic compartments); SP-D and SP-A co-localize in the same Clara cell granules but SP-D is confined to the periphery while SP-A is distributed throughout. Immunogold labeling electron microscopy, double-labeling with anti-SP-A, lysosomal marker co-staining, endocytotic tracer (BSAG) experiments The journal of histochemistry and cytochemistry High 1527377
1994 SP-D assembles as homopolymers of four identical trimeric subunits (dodecamers) with four rod-like arms of ~46 nm, stabilized by interchain disulfide bonds in the N-terminal domain; higher-order multimers (up to 8 molecules) are also observed; trimeric collagenous fragments are released by pepsin digestion, and trimeric subunits by sulfhydryl reduction. Electron microscopy (freeze-drying), hydrodynamic analysis, pepsin digestion, bacterial collagenase digestion, sulfhydryl reduction under non-denaturing conditions, gel filtration The Journal of biological chemistry High 8006040
1994 SP-D potently inhibits hemagglutination activity of influenza A viruses (IAV), causes viral aggregation, enhances neutrophil binding of IAV, and boosts neutrophil respiratory burst; these effects are mediated by the calcium-dependent carbohydrate-binding property of SP-D and SP-D was at least 10-fold more potent than SP-A or MBL in hemagglutination inhibition. Hemagglutination inhibition assay, viral aggregation assay, neutrophil binding assay, respiratory burst assay, EDTA/calcium competition experiments The Journal of clinical investigation High 8040272
1995 SP-D acts as a chemoattractant for human neutrophils and monocytes via its carbohydrate recognition domain (CRD); migration is dose-dependent (peak at ~10⁻¹¹ M), inhibited by maltose but not lactose, and blocked by antibodies to the C-terminal lectin domain, demonstrating that SP-D binds specific saccharide-recognizing sites on these cells. Modified Boyden chamber assay, checkerboard analysis, maltose/lactose competition, antibody blocking, HL-60 differentiation assay American journal of respiratory cell and molecular biology High 7695920
1996 Recombinant human SP-D (rhSP-D) multimers of dodecamers show several-fold greater potency than purified dodecamers alone in causing IAV aggregation and protecting neutrophils from viral deactivation, demonstrating CRD valency-dependent interactions; the propensity to form multimers is determined by the primary structure of human SP-D. Recombinant protein expression in CHO-K1 cells, gel filtration chromatography, electron microscopy, hemagglutination inhibition assay, neutrophil protection assay The American journal of physiology High 8944718
1999 The trimeric carbohydrate recognition domain (CRD) of SP-D is sufficient for neutrophil chemotactic activity (peak at 10⁻¹⁰ M), and this activity is abolished by 20 mM maltose but not lactose, indicating that the saccharide-binding function of the CRD mediates the chemoattractant effect. Recombinant CRD expression in E. coli, gel filtration, Boyden chamber chemotaxis assay, maltose/lactose competition, preincubation cross-inhibition experiments The American journal of physiology High 9887065
2000 SP-D deficiency in mice results in multiple abnormalities in surfactant metabolism: 3–4-fold excess surfactant lipids in airspaces, faster conversion of large- to small-aggregate surfactant, faster clearance of SP-D itself (t½ 7 h vs. 13 h in wild-type), and ~3-fold higher net clearance rates of saturated phosphatidylcholine, indicating SP-D regulates surfactant lipid homeostasis. SP-D gene-targeted knockout mice, radiolabeled lipid incorporation and clearance, bronchoalveolar lavage fractionation, surface tension measurement American journal of physiology. Lung cellular and molecular physiology High 10956621
2000 Pulmonary-specific expression of SP-D in SP-D-deficient mice corrects the surfactant phospholipid accumulation and decreases phosphatidylcholine incorporation, confirming SP-D acts locally in the lung to regulate alveolar phospholipid homeostasis; overexpression of SP-D in wild-type mice does not alter lung morphology or macrophage abundance. Transgenic mice expressing rat SP-D under the human SP-C promoter, breeding with SP-D-/- mice, bronchoalveolar lavage lipid analysis, lung morphology American journal of physiology. Lung cellular and molecular physiology High 10666121
2001 Disulfide cross-linked SP-D oligomers (dodecamers) are required in vivo for regulation of surfactant phospholipid homeostasis and prevention of emphysema and foamy macrophages; monomeric/trimeric SP-D (Cys15/20→Ser mutant) fails to rescue the SP-D null phenotype and, when expressed in wild-type mice, reduces endogenous oligomers and induces emphysema and foamy macrophages without phospholipid abnormalities. Transgenic mice expressing Cys→Ser mutant SP-D, bronchoalveolar lavage lipid analysis, lung histology (emphysema quantification), Western blot The Journal of biological chemistry High 11278637
2001 SP-D and GM-CSF regulate surfactant phospholipid homeostasis by distinct, approximately additive mechanisms: SP-D deficiency does not impair alveolar macrophage degradation of DPPC (unlike GM-CSF deficiency), and GM-CSF expression in SP-D/GM-CSF double-null mice corrects GM-CSF-dependent abnormalities but not the SP-D-dependent emphysema and foamy macrophages. Double knockout mice (SP-D-/-, GM-CSF-/-), GM-CSF transgenic rescue, bronchoalveolar lavage lipid analysis, macrophage DPPC degradation assay, lung histology American journal of physiology. Lung cellular and molecular physiology High 11504698
2001 SP-D counteracts the inhibitory effect of SP-A on phospholipid secretion by alveolar type II cells by competing with SP-A for high-affinity binding sites on type II cells; this competition is mediated via SP-D-associated lipids (activity destroyed by butanol extraction) and involves direct SP-A–SP-D binding on nitrocellulose. Alveolar type II cell secretion assay, 125I-SP-A competitive binding, antibody blocking, heat inactivation, butanol lipid extraction, nitrocellulose binding overlay The Biochemical journal Medium 1930130
2002 SP-D loss-of-function in SP-D-/- mice results in persistent T cell activation specifically in the lung (increased CD4+ and CD8+ T cells expressing CD69 and CD25, increased BAL CD4 lymphocytes), with upregulated IL-12 and IL-6, while splenic T cells remain unactivated, indicating SP-D plays a local immunoregulatory role suppressing T cell activation. SP-D gene-targeted mice, flow cytometry (CD4, CD8, CD69, CD25 markers), RNase protection assay, RT-PCR, ELISA for cytokines, morphometric analysis American journal of respiratory cell and molecular biology High 12091242
2002 Human SP-D binds Mycoplasma pneumoniae with high affinity via its carbohydrate recognition domain: binding requires Ca2+, is inhibited by mannose/glucose/maltose/inositol, and a tandem CRD mutant (E321Q/N323D) fails to bind M. pneumoniae lipids; protease treatment does not abolish Ca2+-dependent binding, indicating lipid components of the bacterial membrane are the primary SP-D targets. Solid-phase binding assays, Ca2+/EDTA competition, sugar competition, protease pretreatment, 2D-TLC overlay with purified lipids, site-directed mutagenesis of CRD The Journal of biological chemistry High 11916969
2002 The carbohydrate recognition domains (CRDs) of both SP-D and conglutinin are required for antiviral host defense in vivo: an SP-D/conglutinin CRD chimera corrects phospholipid accumulation and IAV clearance defects in SP-D-/- mice but does not rescue emphysema or ongoing inflammation, demonstrating that CRD-mediated antimicrobial function and lipid homeostasis/emphysema prevention involve distinct molecular mechanisms. Transgenic chimeric protein expression in SP-D-/- mice, bronchoalveolar lavage lipid analysis, IAV clearance assay, inflammatory cell quantification, lung histology The Journal of biological chemistry High 11956209
2002 SP-D conditional replacement in adult SP-D-/- mice restores alveolar SP-D within 3 days and corrects phospholipid abnormalities and macrophage dysfunction, but once emphysema is established it is not reversed, demonstrating that SP-D-dependent surfactant lipid homeostasis and emphysema are mechanistically dissociated processes. Doxycycline-inducible conditional transgenic SP-D expression in SP-D-/- mice, bronchoalveolar lavage lipid analysis, lung morphology at different ages The Journal of biological chemistry High 12163500
2004 NFATc3 and TTF-1 (thyroid transcription factor-1) synergistically activate the Sftpd promoter via a calcineurin/NFAT-dependent enhancer; NFATc3 and TTF-1 co-immunoprecipitate from mouse lung epithelial cells and physically interact in vitro; cyclosporin-sensitive NFAT sites in the Sftpd promoter were identified by gel supershift and DNase I footprinting. Promoter reporter assays, gel supershift, DNase I protection, co-immunoprecipitation, in vitro interaction assay, cyclosporin/VIVIT inhibitor treatments, ionomycin/PMA stimulation The Journal of biological chemistry High 15173172
2005 A common SFTPD polymorphism at codon 11 (Met11Thr) influences SP-D oligomerization: Thr/Thr11 individuals lack the highest molecular weight multimeric form of SP-D in serum, have lower serum SP-D levels, and recombinant Thr11 SP-D also fails to form multimers; high-molecular-weight SP-D multimers preferentially bind intact IAV and bacteria, while monomeric SP-D preferentially binds isolated LPS. SFTPD genotyping, gel filtration chromatography, atomic force microscopy, ELISA, solid-phase binding assays with mannan, IAV, LPS, bacteria, recombinant protein expression Journal of immunology High 15661913
2006 The collagenous domain of SP-D is required for regulation of pulmonary macrophage activation, airspace remodeling, and surfactant lipid homeostasis in vivo, but is not required for assembly of disulfide-stabilized oligomers nor for the innate immune response to influenza A in vivo; a collagen-deletion mutant corrects viral clearance but fails to rescue emphysema and foamy macrophages in Sftpd-/- mice. Transgenic expression of collagen-domain deletion mutant (rSftpdCDM) in wild-type and Sftpd-/- mice, carbohydrate binding assay, bacterial aggregation assay, IAV clearance assay, bronchoalveolar lavage lipid analysis, lung histology The Journal of biological chemistry High 16787926
2006 Phenylalanine 335 (Phe-335) in the human SP-D CRD mediates ring-stacking interactions with aromatic glycosides and extended saccharides (maltotriose, p-nitrophenyl-maltoside) but not with maltose or glucose; substitution with leucine reduces affinity for these ligands while tyrosine or tryptophan substitutions restore it; alanine substitution abolishes binding to mannan or maltose supports; crystal structures show Phe-335 stacking with terminal glucose or nitrophenyl rings. Site-directed mutagenesis, surface plasmon resonance/binding affinity measurements, crystallographic analysis of CRD complexes with maltotriose and p-nitrophenyl-maltoside The Journal of biological chemistry High 16636058
2006 SP-D-deficient mice gain significantly more body weight than wild-type mice (90 mg/week more on normal chow) and have 17% higher fat percentage, and serum SP-D levels are inversely associated with BMI and waist circumference in humans, indicating SP-D participates in regulation of systemic lipid/energy homeostasis. Spd-/- mouse feeding study with body weight time-course, fat percentage measurement, twin population cohort analysis with multiple regression for serum SP-D vs. BMI/weight/waist Scandinavian journal of immunology Medium 17083619
2006 SP-D-deficient (Sftpd-/-) mice show NH2-terminal and collagenous domain requirement for SP-D-dependent regulation of surfactant homeostasis: neither full-length SP-A, nor an NH2-rSftpa/d chimera (SP-A NH2+collagen with SP-D neck+CRD), rescues the increased phosphatidylcholine, emphysema, or macrophage infiltration in Sftpd-/- mice; furthermore, emphysema in Sftpd-/- mice is not caused solely by MMP-9 or MMP-12 overexpression. Transgenic expression of SP-A and chimeric proteins in Sftpd-/- mice, bronchoalveolar lavage lipid analysis, lung morphology, double-KO with Mmp9-/- and Mmp12-/- American journal of physiology. Lung cellular and molecular physiology High 16500946
2009 SP-D binds the membrane-proximal immunoglobulin-like domain (D3) of SIRPα and SIRPβ in a calcium- and carbohydrate-dependent manner via specific N-glycosylated residues on D3; this binding site is distinct from the CD47 binding site on the membrane-distal D1 domain; SP-D also binds SIRPα on human neutrophils. Domain-deleted SIRPα mutant binding assays, N-glycosylation site mutagenesis, solid-phase binding assays, binding to differentiated neutrophil-like cells The Journal of biological chemistry High 22511785
2009 Trimeric and multimeric forms of SP-D show distinct ligand binding: trimeric SP-D subunits bind LPS, PGN, and endogenous lipoproteins (LDL, oxLDL, HDL) with greater affinity, while multimeric SP-D preferentially binds mannan and LTA; the two forms are only partially interconvertible with distinct disulfide crosslinking patterns. ManNAc-affinity chromatography isolation of trimeric SP-D, gel filtration, solid-phase ELISA binding assays, non-reducing SDS-PAGE disulfide analysis Molecular immunology Medium 19577304
2012 MMP-9 cleaves SP-D in vitro and this cleavage abrogates its innate immune functions including bacterial aggregation and enhancement of phagocytosis by alveolar macrophages; however, MMP-9-cleaved SP-D retains LPS binding activity whereas neutrophil elastase (NE)-cleaved SP-D does not, indicating distinct cleavage sites and differential loss of function. In vitro protease cleavage assay, bacterial aggregation assay, macrophage phagocytosis assay, solid-phase LPS binding ELISA, calcium-concentration-dependent cleavage comparison PloS one Medium 22860023
2018 SP-D assembles into a mixture of trimers, hexamers, dodecamers, and higher-order oligomers; dodecamers account for >50% by mass; dodecamer formation is stabilized by non-covalent, ionic, and hydrophobic interactions between N-terminal domains of two hexamers; acidic conditions increase dodecamer proportion with conformational compaction. Atomic force microscopy (AFM), non-reducing SDS-PAGE, gel filtration, pH manipulation experiments with full-length recombinant human SP-D and patient-derived proteinosis SP-D Journal of molecular biology High 29626540
2018 SP-D directly binds eosinophil membranes and inhibits extracellular DNA trap (EET) formation in a concentration- and carbohydrate-dependent manner; S-nitrosylation of SP-D (simulating iNOS-mediated oxidative modification in asthmatic airways) causes de-oligomerization and abolishes its ability to suppress EET formation. Recombinant SP-D binding to eosinophils (confocal imaging), EET formation assay, in vivo SP-D S-nitrosylation in allergic/ozone-challenged mice, in vitro iNOS-mediated S-nitrosylation, non-reducing SDS-PAGE oligomer analysis Journal of leukocyte biology High 29733456
2019 SP-D suppresses LPS-mediated NETosis in human neutrophils by binding to LPS; SP-D deficiency in mice leads to excess NET formation in LPS-inflamed lungs; NETs inhibit surface-active properties of lung surfactant in the absence of SP-D; SP-D can reverse NET-mediated surfactant inhibition and restore its biophysical properties. SP-D binding to LPS (solid-phase assay), NETosis quantification in human neutrophils, Sftpd-/- mouse LPS model, surfactant biophysical function assay, NET-surfactant inhibition experiments Communications biology High 31872075

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Surfactant proteins SP-A and SP-D: structure, function and receptors. Molecular immunology 413 16213021
1994 Evidence for a protective role of pulmonary surfactant protein D (SP-D) against influenza A viruses. The Journal of clinical investigation 267 8040272
1994 Molecular structure of pulmonary surfactant protein D (SP-D). The Journal of biological chemistry 187 8006040
1989 Purification and biochemical characterization of CP4 (SP-D), a collagenous surfactant-associated protein. Biochemistry 176 2675969
1992 Immunocytochemical localization of surfactant protein D (SP-D) in type II cells, Clara cells, and alveolar macrophages of rat lung. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 166 1527377
2005 The lung collectins, SP-A and SP-D, modulate pulmonary innate immunity. Molecular immunology 157 15589315
2000 Polymorphisms of human SP-A, SP-B, and SP-D genes: association of SP-B Thr131Ile with ARDS. Clinical genetics 154 11076040
2012 An Insight into the Diverse Roles of Surfactant Proteins, SP-A and SP-D in Innate and Adaptive Immunity. Frontiers in immunology 150 22701116
1999 Novel, non-radioactive, simple and multiplex PCR-cRFLP methods for genotyping human SP-A and SP-D marker alleles. Disease markers 141 10689550
1996 Interactions of recombinant human pulmonary surfactant protein D and SP-D multimers with influenza A. The American journal of physiology 129 8944718
2005 A common polymorphism in the SFTPD gene influences assembly, function, and concentration of surfactant protein D. Journal of immunology (Baltimore, Md. : 1950) 124 15661913
1998 Structure, biologic properties, and expression of surfactant protein D (SP-D). Biochimica et biophysica acta 122 9813367
2021 SP-A and SP-D: Dual Functioning Immune Molecules With Antiviral and Immunomodulatory Properties. Frontiers in immunology 121 33542724
2002 Immunolocalization of surfactant protein-D (SP-D) in human fetal, newborn, and adult tissues. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 111 11967276
1998 Organization of the human SP-A and SP-D loci at 10q22-q23. Physical and radiation hybrid mapping reveal gene order and orientation. American journal of respiratory cell and molecular biology 106 9490653
2016 Comparative Study of Circulating MMP-7, CCL18, KL-6, SP-A, and SP-D as Disease Markers of Idiopathic Pulmonary Fibrosis. Disease markers 104 27293304
1993 Genomic organization of human surfactant protein D (SP-D). SP-D is encoded on chromosome 10q22.2-23.1. The Journal of biological chemistry 99 8428971
2003 Surfactant protein D (SP-D) serum levels in patients with community-acquired pneumonia. Clinical immunology (Orlando, Fla.) 98 12865068
1994 Surfactant proteins A (SP-A) and D (SP-D): levels in human amniotic fluid and localization in the fetal membranes. Biochimica et biophysica acta 97 8305484
2005 Susceptibility of mice genetically deficient in the surfactant protein (SP)-A or SP-D gene to pulmonary hypersensitivity induced by antigens and allergens of Aspergillus fumigatus. Journal of immunology (Baltimore, Md. : 1950) 90 15905537
1995 Interactions of pulmonary surfactant protein D (SP-D) with human blood leukocytes. American journal of respiratory cell and molecular biology 89 7695920
2000 Surfactant metabolism in SP-D gene-targeted mice. American journal of physiology. Lung cellular and molecular physiology 87 10956621
2010 Prescreening based on the presence of CT-scan abnormalities and biomarkers (KL-6 and SP-D) may reduce severe radiation pneumonitis after stereotactic radiotherapy. Radiation oncology (London, England) 86 20459699
1991 Human surfactant protein D: SP-D contains a C-type lectin carbohydrate recognition domain. Archives of biochemistry and biophysics 83 1898081
2004 Effects of ageing and smoking on SP-A and SP-D levels in bronchoalveolar lavage fluid. The European respiratory journal 81 15572540
1998 KGF increases SP-A and SP-D mRNA levels and secretion in cultured rat alveolar type II cells. American journal of respiratory cell and molecular biology 81 9476903
1991 Developmental expression of pulmonary surfactant protein D (SP-D). American journal of respiratory cell and molecular biology 71 1878250
2007 Truncated recombinant human SP-D attenuates emphysema and type II cell changes in SP-D deficient mice. Respiratory research 70 17915009
1992 The major glycolipid recognized by SP-D in surfactant is phosphatidylinositol. Biochemistry 70 1457414
2012 Mice deficient in surfactant protein A (SP-A) and SP-D or in TLR2 manifest delayed parturition and decreased expression of inflammatory and contractile genes. Endocrinology 69 23183169
2000 Pulmonary-specific expression of SP-D corrects pulmonary lipid accumulation in SP-D gene-targeted mice. American journal of physiology. Lung cellular and molecular physiology 69 10666121
2015 The usefulness of KL-6 and SP-D for the diagnosis and management of chronic hypersensitivity pneumonitis. Respiratory medicine 66 26481343
2010 Role of surfactant protein A and D (SP-A and SP-D) in human antiviral host defense. Frontiers in bioscience (Scholar edition) 60 20036966
2005 Surfactant proteins SP-A and SP-D in human health and disease. Archivum immunologiae et therapiae experimentalis 59 16314824
2008 Chronic obstructive pulmonary disease and inhaled steroids alter surfactant protein D (SP-D) levels: a cross-sectional study. Respiratory research 58 18226251
2001 Activity of pulmonary surfactant protein-D (SP-D) in vivo is dependent on oligomeric structure. The Journal of biological chemistry 58 11278637
2003 Attenuated allergic airway hyperresponsiveness in C57BL/6 mice is associated with enhanced surfactant protein (SP)-D production following allergic sensitization. Respiratory research 57 14748931
1993 Assignment of the human pulmonary surfactant protein D gene (SFTP4) to 10q22-q23 close to the surfactant protein A gene cluster. Genomics 55 8406480
2010 Susceptibility of mice genetically deficient in SP-A or SP-D gene to invasive pulmonary aspergillosis. Molecular immunology 52 20413160
2004 GM-CSF mediates alveolar epithelial type II cell changes, but not emphysema-like pathology, in SP-D-deficient mice. American journal of physiology. Lung cellular and molecular physiology 51 15310555
2016 Surfactant proteins, SP-A and SP-D, in respiratory fungal infections: their role in the inflammatory response. Respiratory research 49 27250970
2012 Surfactant protein D (SP-D) alters cellular uptake of particles and nanoparticles. Nanotoxicology 48 22551051
2005 Polymorphisms in the human surfactant protein-D (SFTPD) gene: strong evidence that serum levels of surfactant protein-D (SP-D) are genetically influenced. Immunogenetics 48 15700120
2002 Lymphocyte activation in the lungs of SP-D null mice. American journal of respiratory cell and molecular biology 46 12091242
2019 SP-D attenuates LPS-induced formation of human neutrophil extracellular traps (NETs), protecting pulmonary surfactant inactivation by NETs. Communications biology 45 31872075
2006 Correction of pulmonary abnormalities in Sftpd-/- mice requires the collagenous domain of surfactant protein D. The Journal of biological chemistry 45 16787926
2004 Nuclear factor of activated T cells regulates transcription of the surfactant protein D gene (Sftpd) via direct interaction with thyroid transcription factor-1 in lung epithelial cells. The Journal of biological chemistry 45 15173172
1991 Ontogeny of surfactant apoprotein D, SP-D, in the rat lung. Biochimica et biophysica acta 45 2049389
2002 Complementation of pulmonary abnormalities in SP-D(-/-) mice with an SP-D/conglutinin fusion protein. The Journal of biological chemistry 44 11956209
2002 Clinical significance of serum surfactant protein D (SP-D) in patients with polymyositis/dermatomyositis: correlation with interstitial lung disease. Rheumatology (Oxford, England) 44 12421999
2001 Localization and functions of SP-A and SP-D at mucosal surfaces. Pediatric pathology & molecular medicine 44 11486736
1992 Binding specificity of lung surfactant protein SP-D for glucosylceramide. Biochemical and biophysical research communications 43 1530650
2018 Genetic Association of Pulmonary Surfactant Protein Genes, SFTPA1, SFTPA2, SFTPB, SFTPC, and SFTPD With Cystic Fibrosis. Frontiers in immunology 42 30333828
2001 Pneumocystis carinii pneumonia alters expression and distribution of lung collectins SP-A and SP-D. The Journal of laboratory and clinical medicine 42 11385364
2002 Serum SP-D is a marker of lung injury in rats. American journal of physiology. Lung cellular and molecular physiology 41 11880309
2002 Surfactant proteins SP-A and SP-D as modulators of the allergic inflammation in asthma. Pathobiology : journal of immunopathology, molecular and cellular biology 40 12771511
2002 Human surfactant protein D (SP-D) binds Mycoplasma pneumoniae by high affinity interactions with lipids. The Journal of biological chemistry 39 11916969
2013 Ligands and receptors of lung surfactant proteins SP-A and SP-D. Frontiers in bioscience (Landmark edition) 37 23747872
2007 The immunoregulatory roles of lung surfactant collectins SP-A, and SP-D, in allergen-induced airway inflammation. Immunobiology 37 17544824
2020 Exogenous pulmonary surfactant: A review focused on adjunctive therapy for severe acute respiratory syndrome coronavirus 2 including SP-A and SP-D as added clinical marker. Current opinion in colloid & interface science 36 33390762
2017 Morphology and molecular characterization of Demidospermus spirophallus n. sp., D. prolixus n. sp. (Monogenea: Dactylogyridae) and a redescription of D. anus in siluriform catfish from Brazil. Journal of helminthology 36 28382887
2013 Lung surfactant protein D (SP-D) response and regulation during acute and chronic lung injury. Lung 36 23435873
2006 Surfactant protein D of the innate immune defence is inversely associated with human obesity and SP-D deficiency infers increased body weight in mice. Scandinavian journal of immunology 36 17083619
2002 Reversibility of pulmonary abnormalities by conditional replacement of surfactant protein D (SP-D) in vivo. The Journal of biological chemistry 36 12163500
2001 SP-D and GM-CSF regulate surfactant homeostasis via distinct mechanisms. American journal of physiology. Lung cellular and molecular physiology 36 11504698
2012 Linking surfactant protein SP-D and IL-13: implications in asthma and allergy. Molecular immunology 35 23220073
2002 Structural requirements for SP-D function in vitro and in vivo: therapeutic potential of recombinant SP-D. Immunobiology 35 12396020
2015 DNA vaccine molecular adjuvants SP-D-BAFF and SP-D-APRIL enhance anti-gp120 immune response and increase HIV-1 neutralizing antibody titers. Journal of virology 34 25631080
2010 SP-D and regulation of the pulmonary innate immune system in allergic airway changes. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 34 20447075
2004 High resolution mass spectrometric alveolar proteomics: identification of surfactant protein SP-A and SP-D modifications in proteinosis and cystic fibrosis patients. Proteomics 34 15274124
2002 Lung surfactant protein D (SP-D) and the molecular diverted descendants: conglutinin, CL-43 and CL-46. Immunobiology 34 12396011
2012 MMP-9 cleaves SP-D and abrogates its innate immune functions in vitro. PloS one 33 22860023
2016 YKL-40, CCL18 and SP-D predict mortality in patients hospitalized with community-acquired pneumonia. Respirology (Carlton, Vic.) 32 27782361
1999 Recombinant SP-D carbohydrate recognition domain is a chemoattractant for human neutrophils. The American journal of physiology 32 9887065
2018 Oxidative damage of SP-D abolishes control of eosinophil extracellular DNA trap formation. Journal of leukocyte biology 31 29733456
2009 Multimeric and trimeric subunit SP-D are interconvertible structures with distinct ligand interaction. Molecular immunology 31 19577304
2006 Contributions of phenylalanine 335 to ligand recognition by human surfactant protein D: ring interactions with SP-D ligands. The Journal of biological chemistry 31 16636058
2016 Surfactant Proteins SP-A and SP-D Ameliorate Pneumonia Severity and Intestinal Injury in a Murine Model of Staphylococcus Aureus Pneumonia. Shock (Augusta, Ga.) 30 26849628
2009 The human lung surfactant proteins A (SP-A) and D (SP-D) interact with apoptotic target cells by different binding mechanisms. Immunobiology 30 19880212
2006 SP-D-deficient mice are resistant to hyperoxia. American journal of physiology. Lung cellular and molecular physiology 30 17158597
1991 Surfactant protein D (SP-D) counteracts the inhibitory effect of surfactant protein A (SP-A) on phospholipid secretion by alveolar type II cells. Interaction of native SP-D with SP-A. The Biochemical journal 30 1930130
2019 Evaluation of the Diagnostic Efficacies of Serological Markers KL-6, SP-A, SP-D, CCL2, and CXCL13 in Idiopathic Interstitial Pneumonia. Respiration; international review of thoracic diseases 29 31665737
2008 Association of polymorphisms in the human surfactant protein-D (SFTPD) gene and postnatal pulmonary adaptation in the preterm infant. Acta paediatrica (Oslo, Norway : 1992) 27 18785967
2022 Surfactant protein D (SP-D) as a biomarker of SARS-CoV-2 infection. Clinica chimica acta; international journal of clinical chemistry 26 36341812
2021 Serial Measurements of Circulating KL-6, SP-D, MMP-7, CA19-9, CA-125, CCL18, and Periostin in Patients with Idiopathic Pulmonary Fibrosis Receiving Antifibrotic Therapy: An Exploratory Study. Journal of clinical medicine 26 34501312
2011 Assessment of the antiviral properties of recombinant porcine SP-D against various influenza A viruses in vitro. PloS one 26 21935489
2009 Elevated plasma surfactant protein D (SP-D) levels and a direct correlation with anti-severe acute respiratory syndrome coronavirus-specific IgG antibody in SARS patients. Scandinavian journal of immunology 26 19439011
2007 Expression sites of the collectin SP-D suggest its importance in first line host defence: power of combining in situ hybridisation, RT-PCR and immunohistochemistry. Molecular immunology 26 17420052
2001 GM-CSF mediates alveolar macrophage proliferation and type II cell hypertrophy in SP-D gene-targeted mice. American journal of physiology. Lung cellular and molecular physiology 26 11350793
2018 Supramolecular Assembly of Human Pulmonary Surfactant Protein SP-D. Journal of molecular biology 24 29626540
2012 Surfactant protein D (Sp-D) binds to membrane-proximal domain (D3) of signal regulatory protein α (SIRPα), a site distant from binding domain of CD47, while also binding to analogous region on signal regulatory protein β (SIRPβ). The Journal of biological chemistry 24 22511785
2011 SP-A1, SP-A2 and SP-D gene polymorphisms in severe acute respiratory syncytial infection in Chilean infants. Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases 24 21601013
2004 Binding and agglutination of Streptococcus pneumoniae by human surfactant protein D (SP-D) vary between strains, but SP-D fails to enhance killing by neutrophils. Infection and immunity 24 14742512
2009 Genetic variants in surfactant, pulmonary-associated protein D (SFTPD) and Japanese susceptibility to ulcerative colitis. Inflammatory bowel diseases 22 19340882
2014 Surfactant protein SP-D modulates activity of immune cells: proteomic profiling of its interaction with eosinophilic cells. Expert review of proteomics 21 24697551
2013 Donor surfactant protein D (SP-D) polymorphisms are associated with lung transplant outcome. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 21 23841811
2010 Surfactant protein (SP)-A and SP-D as antimicrobial and immunotherapeutic agents. Recent patents on anti-infective drug discovery 21 20230362
2006 Neither SP-A nor NH2-terminal domains of SP-A can substitute for SP-D in regulation of alveolar homeostasis. American journal of physiology. Lung cellular and molecular physiology 21 16500946
2004 The genes encoding bovine SP-A, SP-D, MBL-A, conglutinin, CL-43 and CL-46 form a distinct collectin locus on Bos taurus chromosome 28 (BTA28) at position q.1.8-1.9. Animal genetics 21 15265076
2010 Serum-surfactant SP-D correlates inversely to lung function in cystic fibrosis. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society 20 20457545

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