{"gene":"SFTPD","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":1989,"finding":"SP-D (CP4) was identified as a distinct collagenous glycoprotein synthesized by rat type II pulmonary epithelial cells, forming high apparent molecular mass complexes of disulfide-bonded trimers of 43-kDa subunits, and was formally designated 'surfactant protein D'.","method":"Biochemical purification (BaSO4 adsorption, reverse-phase HPLC), amino acid analysis, 2D-IEF/SDS-PAGE, gel filtration, CNBr peptide sequencing","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal biochemical methods establishing primary structure and quaternary assembly","pmids":["2675969"],"is_preprint":false},{"year":1991,"finding":"Human SP-D contains a C-type lectin carbohydrate recognition domain (CRD) with calcium-dependent saccharide binding, confirmed by cDNA sequencing, immunoprecipitation of translation products, and peptide antibody reactivity; the CRD contains conserved cysteine residues and shows high homology with mannose-binding subfamily C-type lectins.","method":"cDNA library screening, DNA sequencing, immunoprecipitation, synthetic peptide antibodies, amino-terminal microsequencing","journal":"Archives of biochemistry and biophysics","confidence":"High","confidence_rationale":"Tier 1 — direct CRD identification via sequencing and functional antibody validation","pmids":["1898081"],"is_preprint":false},{"year":1991,"finding":"Native 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 to type II cells; this activity requires SP-D-associated lipids and involves direct SP-D–SP-A interaction.","method":"Primary type II cell secretion assay, radiolabeled SP-A competition binding, nitrocellulose overlay, butanol extraction of SP-D","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 — multiple functional assays in primary cells; single lab","pmids":["1930130"],"is_preprint":false},{"year":1991,"finding":"SP-D mRNA and protein first appear in rat lung at gestational day 21 in cuboidal epithelial cells lining immature airspaces, and in adult lung in type II and nonciliated bronchiolar cells, with SP-D secreted into amniotic fluid, establishing developmental expression pattern.","method":"Northern hybridization, immunoperoxidase staining, cell-free translation, affinity chromatography","journal":"American journal of respiratory cell and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization with functional correlation to developmental timing","pmids":["1878250"],"is_preprint":false},{"year":1992,"finding":"SP-D localizes in type II cells (endoplasmic reticulum, Golgi, multivesicular bodies but not lamellar bodies), Clara cells (secretory granules at apical domain), and alveolar macrophages (endocytotic structures); in Clara cells SP-D co-localizes with SP-A in the same granules but is confined to the periphery while SP-A distributes throughout.","method":"Immunogold electron microscopy, double-labeling with anti-SP-A and lysosomal markers, BSAG endocytotic pathway tracing","journal":"Journal of histochemistry and cytochemistry","confidence":"High","confidence_rationale":"Tier 2 — ultrastructural localization with multiple controls and double-labeling","pmids":["1527377"],"is_preprint":false},{"year":1992,"finding":"SP-D binds exclusively to glucosylceramide (GlcCer) among glycolipids tested, in a calcium-dependent and antibody-inhibitable manner; Mg2+ cannot substitute for Ca2+.","method":"TLC overlay with 125I-labeled SP-D, competition assay, antibody inhibition","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — direct ligand binding with specific controls; single lab","pmids":["1530650"],"is_preprint":false},{"year":1992,"finding":"SP-D binds phosphatidylinositol (PI) as its major glycolipid ligand in surfactant in a calcium-dependent, saccharide-inhibitable manner, including binding to PI in lipid bilayer liposomes.","method":"2D-TLC overlay with 125I-SP-D, affinity purification, mass spectrometry, Percoll density gradient liposome binding","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — ligand identified by multiple methods including mass spectrometry and reconstituted bilayer assay","pmids":["1457414"],"is_preprint":false},{"year":1993,"finding":"SP-D is encoded on chromosome 10q22.2-23.1; the collagen domain is encoded on five exons including four tandem 117-bp exons, while the signal peptide/N-terminal domain, CRD, and linking sequence are each on a single exon, consistent with modular evolution.","method":"Genomic clone characterization, sequencing, segregation analysis with HindIII, fluorescence in situ hybridization, PCR with somatic cell hybrids","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — direct genomic sequencing and FISH mapping","pmids":["8428971"],"is_preprint":false},{"year":1994,"finding":"SP-D forms a dodecameric quaternary structure assembled as homopolymers of four identical trimeric subunits, each arm 46 nm long with a globular CRD terminal expansion; interchain disulfide bonds at the N-terminal domain stabilize trimer interactions, and higher-order multimeric assemblies also occur.","method":"Electron microscopy (freeze-dried), hydrodynamic analysis, pepsin digestion, sulfhydryl reduction, bacterial collagenase digestion","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — structural determination by EM and biochemical dissection; foundational paper","pmids":["8006040"],"is_preprint":false},{"year":1994,"finding":"SP-D potently inhibits influenza A virus (IAV) hemagglutination and causes viral aggregation via its calcium-dependent carbohydrate-binding CRD; SP-D enhances neutrophil binding of IAV and respiratory burst, and diminishes neutrophil dysfunction caused by IAV.","method":"Hemagglutination inhibition assay, viral aggregation assay, neutrophil binding assay, respiratory burst measurement, calcium/saccharide inhibition controls","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — multiple functional assays with mechanistic controls; replicated with human, rat and recombinant SP-D","pmids":["8040272"],"is_preprint":false},{"year":1995,"finding":"SP-D acts as a chemoattractant for human neutrophils and monocytes in a dose-dependent, saccharide-inhibitable (maltose-sensitive) manner via interactions involving the carboxy-terminal lectin domain.","method":"Modified Boyden chamber chemotaxis assay, checkerboard analysis, antibody and sugar inhibition","journal":"American journal of respiratory cell and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 — direct functional assay with domain-specific antibody and sugar inhibition","pmids":["7695920"],"is_preprint":false},{"year":1996,"finding":"Higher-order multimers of human SP-D (multimers of dodecamers) are several-fold more potent than dodecamers at causing IAV aggregation and protecting neutrophils from IAV deactivation, demonstrating valency-dependent CRD interactions; the propensity to form multimers is determined by primary structure.","method":"Recombinant hSP-D expression in CHO cells, gel filtration, electron microscopy, hemagglutination inhibition, neutrophil protection assay","journal":"The American journal of physiology","confidence":"High","confidence_rationale":"Tier 1 — structure-function with recombinant protein fractionation; multiple assays","pmids":["8944718"],"is_preprint":false},{"year":1999,"finding":"The trimeric carbohydrate recognition domain (CRD) of SP-D is sufficient for chemotactic activity toward neutrophils, with peak activity at 10^-10 M; activity is abolished by 20 mM maltose, indicating CRD-dependent recognition.","method":"Recombinant neck+CRD expression in E. coli, gel-filtration characterization, Boyden chamber chemotaxis, maltose inhibition","journal":"The American journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 — domain-specific recombinant protein with sugar inhibition; single lab","pmids":["9887065"],"is_preprint":false},{"year":2000,"finding":"SP-D deficiency causes a 3-4 fold increase in alveolar surfactant lipids associated with accelerated conversion of large- to small-aggregate surfactant; pulmonary-specific transgenic re-expression of SP-D corrects the lipid accumulation, demonstrating that SP-D acts locally to regulate surfactant phospholipid homeostasis.","method":"SP-D gene-targeted mice, SP-C promoter-driven transgene, bronchoalveolar lavage phospholipid measurements, radiolabeled phospholipid kinetics","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"High","confidence_rationale":"Tier 2 — genetic rescue experiment with quantitative metabolic readouts; two complementary papers","pmids":["10956621","10666121"],"is_preprint":false},{"year":2001,"finding":"Dodecameric (disulfide cross-linked oligomeric) assembly of SP-D is required for regulation of surfactant phospholipid homeostasis and prevention of emphysema and foamy macrophages in vivo; trimeric SP-D (Cys15/20 → Ser mutant) fails to rescue these phenotypes but does not affect antiviral activity.","method":"Transgenic mice expressing Cys15/20Ser mutant rSP-D in SP-D null background, bronchoalveolar lavage lipid and morphological analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — in vivo domain/mutagenesis dissection with clear phenotypic readouts","pmids":["11278637"],"is_preprint":false},{"year":2001,"finding":"SP-D and GM-CSF regulate surfactant homeostasis by distinct mechanisms: double-knockout mice show approximately additive phospholipid accumulation, and GM-CSF expression corrects GM-CSF-dependent catabolism defects but not SP-D-null lung pathology.","method":"SP-D/GM-CSF double knockout mice, GM-CSF lung-selective transgene rescue, saturated phosphatidylcholine pool size measurements","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"High","confidence_rationale":"Tier 2 — epistasis by double knockout plus transgenic rescue; independent pathways established","pmids":["11504698"],"is_preprint":false},{"year":2001,"finding":"GM-CSF mediates alveolar macrophage proliferation and type II cell hypertrophy in SP-D null mice; double null SP-D/GM-CSF mice show large but not foamy macrophages and mostly normal type II cells, while emphysema persists, separating GM-CSF-dependent from GM-CSF-independent SP-D functions.","method":"SP-D/GM-CSF double knockout breeding, BAL analysis, electron and light microscopy","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"High","confidence_rationale":"Tier 2 — epistasis double knockout with multiple cellular readouts","pmids":["11350793"],"is_preprint":false},{"year":2002,"finding":"Human SP-D binds Mycoplasma pneumoniae via calcium-dependent, carbohydrate-recognition-domain-mediated interactions with bacterial membrane lipids (not proteins); a CRD tandem mutant (E321Q/N323D) abolishes binding, directly implicating the CRD.","method":"Ca2+/EGTA-dependent binding assays, protease pre-treatment of membranes, 2D-TLC overlay, CRD mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — active-site mutagenesis with reconstituted binding assay","pmids":["11916969"],"is_preprint":false},{"year":2002,"finding":"Restoring SP-D expression in adult SP-D null mice via doxycycline-regulated transgene corrects surfactant lipid abnormalities and alveolar macrophage phenotype within days, but established emphysema is not reversed; loss of SP-D in corrected adults causes focal emphysema but not phospholipid abnormalities, showing these pathways are separable.","method":"Conditional doxycycline-regulated transgene in SP-D null mice, BAL lipid assays, morphometric analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reversibility experiment separates mechanistic pathways","pmids":["12163500"],"is_preprint":false},{"year":2002,"finding":"SP-D/conglutinin chimera (SP-D N-terminal/collagen + conglutinin neck+CRD) corrects surfactant phospholipid abnormalities and viral clearance defects in SP-D null mice but does not correct ongoing lung inflammation and emphysema, indicating distinct roles for CRD identity versus N-terminal domains in different SP-D functions.","method":"Chimeric transgene expression in SP-D null mice, BAL lipid assay, influenza A clearance assay, lung morphology","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — domain-swap chimera in vivo with multiple phenotypic endpoints","pmids":["11956209"],"is_preprint":false},{"year":2002,"finding":"SP-D null mice develop persistent pulmonary T cell activation (increased CD4+ and CD8+ T cells expressing CD69 and CD25, elevated BAL CD4 lymphocytes, increased IL-12 and IL-6), demonstrating a local immunoregulatory role for SP-D in suppressing T cell responses in vivo.","method":"Flow cytometry of intrapulmonary lymphocytes from SP-D-/- mice, RNase protection assay, RT-PCR, ELISA for cytokines","journal":"American journal of respiratory cell and molecular biology","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function mouse model with multiple immunological readouts","pmids":["12091242"],"is_preprint":false},{"year":2004,"finding":"NFATc3 regulates SP-D gene (Sftpd) transcription via an NFAT-dependent enhancer in the Sftpd promoter; NFATc3 and TTF-1 synergize, co-immunoprecipitate, and physically interact in vitro to activate Sftpd transcription in lung epithelial cells.","method":"Promoter-reporter assays, gel supershift/DNase I footprinting, calcineurin/cyclosporin/VIVIT inhibition, co-immunoprecipitation, in vitro protein interaction","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — transcriptional mechanism established by promoter assays, gel shift, co-IP, and in vitro interaction","pmids":["15173172"],"is_preprint":false},{"year":2004,"finding":"GM-CSF is required for type II cell hyperplasia and hypertrophy in SP-D-deficient mice but not for emphysema development; emphysema-like changes in SP-D null mice are independent of GM-CSF-dependent macrophage activity.","method":"SP-D/GM-CSF double knockout mice, design-based stereology at light and electron microscope levels","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"High","confidence_rationale":"Tier 2 — epistasis double knockout with quantitative stereological analysis","pmids":["15310555"],"is_preprint":false},{"year":2005,"finding":"A common SFTPD polymorphism at codon 11 (Met11Thr) influences SP-D oligomerization: Thr11 SP-D lacks the highest molecular weight multimeric form, has lower serum levels, and shows preferential binding to isolated LPS rather than intact bacteria/viruses, whereas Met11 multimers preferentially bind intact organisms.","method":"Genotyping, gel filtration, atomic force microscopy of purified protein, ELISA, mannan- and virus-binding assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 — AFM structural analysis combined with functional binding assays and human genotype-phenotype correlation","pmids":["15661913"],"is_preprint":false},{"year":2006,"finding":"The collagenous domain of SP-D is required for regulation of pulmonary macrophage activation, airspace remodeling, and surfactant lipid homeostasis in vivo, but is dispensable for assembly of disulfide-stabilized oligomers and for innate immune response to influenza A.","method":"Collagen deletion mutant SP-D transgene in wild-type and Sftpd-/- mice, BAL lipid assay, influenza A clearance, lung morphology, surfactant ultrastructure","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — domain deletion mutant in vivo with multiple phenotypic readouts","pmids":["16787926"],"is_preprint":false},{"year":2006,"finding":"Phenylalanine 335 in the SP-D CRD mediates preferential binding to aromatic glycosides and maltotriose via ring-stacking interactions; Phe335Leu substitution reduces affinity for maltotriose and p-nitrophenyl-maltoside, and Phe335Ala abolishes mannan binding; crystallographic analysis shows stacking of the terminal glucose or nitrophenyl ring with the Phe335 aromatic ring.","method":"Site-directed mutagenesis, fluorescence polarization binding assay, crystallographic analysis of neck+CRD with ligands","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus mutagenesis confirming mechanism","pmids":["16636058"],"is_preprint":false},{"year":2006,"finding":"Neither full-length SP-A nor chimeric NH2-SP-A/SP-D (SP-A N-terminal+collagen fused to SP-D neck+CRD) can substitute for SP-D in correcting emphysema, foamy macrophages, or lipid accumulation in SP-D null mice; SP-D N-terminal and collagen domains are required for proper oligomerization and surfactant lipid association.","method":"Transgenic expression of chimeric proteins in Sftpd-/- mice, BAL lipid/protein assays, lung morphology","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"High","confidence_rationale":"Tier 2 — domain-swap chimera in vivo; multiple null controls","pmids":["16500946"],"is_preprint":false},{"year":2009,"finding":"SP-D binds to the membrane-proximal immunoglobulin-like domain (D3) of SIRPα in a calcium- and carbohydrate-dependent manner via specific N-glycosylated residues on D3; SP-D also binds the analogous D3 domain of SIRPβ; the SP-D binding site on SIRPα is distinct from the CD47 binding site on D1.","method":"Domain-deleted SIRPα/SIRPβ mutant binding assays, N-glycosylation site mutagenesis, binding to SIRPα on human neutrophils and differentiated neutrophil-like cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — domain deletion and glycosylation mutagenesis with cell surface binding validation","pmids":["22511785"],"is_preprint":false},{"year":2012,"finding":"MMP-9 cleaves SP-D in vitro, abolishing its ability to aggregate bacteria and enhance phagocytosis by alveolar macrophages, while preserving LPS binding; MMP-9 cleaves SP-D more efficiently than neutrophil elastase at physiological calcium concentrations.","method":"In vitro protease cleavage assay, bacterial aggregation assay, macrophage phagocytosis assay, solid-phase LPS binding","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — multiple functional readouts; in vitro only","pmids":["22860023"],"is_preprint":false},{"year":2018,"finding":"SP-D directly binds to eosinophil membranes in a concentration- and carbohydrate-dependent manner and inhibits eosinophil extracellular DNA trap formation; S-nitrosylation of SP-D (mimicking iNOS/oxidative conditions in asthma) causes de-oligomerization of SP-D and abolishes its ability to inhibit DNA trap formation.","method":"Confocal imaging with recombinant SP-D, murine and human eosinophil assays, iNOS inhibition, S-nitrosylation in vitro, Sftpd-/- mice with allergen/ozone challenge","journal":"Journal of leukocyte biology","confidence":"High","confidence_rationale":"Tier 2 — direct binding shown by imaging, mechanistic PTM (S-nitrosylation) established in vitro and in vivo","pmids":["29733456"],"is_preprint":false},{"year":2018,"finding":"Dodecamers are the predominant SP-D oligomeric form (>50% by mass); dodecamer formation requires two hexamers as a minimal unit and is stabilized by non-covalent, ionic, and hydrophobic interactions between N-terminal domains and proximal collagen stems; acidic conditions promote compact dodecamer configuration.","method":"Atomic force microscopy (AFM) of recombinant and patient-derived hSP-D, electrophoresis, comparative analysis at different pH","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — direct structural analysis by AFM with quantitative assessment","pmids":["29626540"],"is_preprint":false},{"year":2019,"finding":"SP-D attenuates LPS-mediated NETosis in human neutrophils by binding LPS; SP-D deficiency in mice leads to excess NET formation in lungs during LPS-mediated inflammation; NETs inhibit pulmonary surfactant biophysical function in the absence of SP-D, and SP-D reverses NET-mediated surfactant inhibition.","method":"Human neutrophil NETosis assay with recombinant SP-D, Sftpd-/- mouse LPS model, surfactant biophysical assay (surface activity measurement)","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 2 — in vitro mechanism confirmed in vivo in knockout model with biophysical functional readout","pmids":["31872075"],"is_preprint":false},{"year":1998,"finding":"KGF increases SP-D mRNA and protein secretion in rat alveolar type II cells in primary culture at the air-liquid interface; TPA+terbutaline stimulates phosphatidylcholine and SP-A secretion but not SP-D, indicating SP-D secretion is regulated by a distinct pathway from SP-A.","method":"Primary rat type II cell culture, Northern blot, ELISA for SP-D protein in apical medium, [3H]PC secretion assay","journal":"American journal of respiratory cell and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 — direct secretion measurement with pharmacological dissection; single lab","pmids":["9476903"],"is_preprint":false}],"current_model":"SP-D (SFTPD) is a collagen-containing C-type lectin collectin secreted by type II pneumocytes and Clara cells that assembles as disulfide-stabilized trimers, dodecamers, and higher-order multimers; its N-terminal/collagen domains govern oligomerization and surfactant phospholipid homeostasis (via locally regulating alveolar macrophage function), while its homotrimeric carbohydrate recognition domain (CRD), with Phe335 as a critical stacking residue, mediates calcium-dependent binding to glucosylceramide, phosphatidylinositol, bacterial lipids, and viral hemagglutinin—enabling pathogen aggregation, neutrophil and monocyte chemoattraction, NETosis suppression, and SIRPα/SIRPβ receptor engagement—and its transcription is co-activated by NFATc3 in complex with TTF-1; post-translational S-nitrosylation disrupts oligomerization and abrogates immune-regulatory function, and cleavage by MMP-9 destroys bactericidal activities while preserving LPS binding."},"narrative":{"teleology":[{"year":1989,"claim":"Identification of SP-D as a distinct collagenous surfactant glycoprotein that forms disulfide-bonded trimers of 43 kDa subunits resolved the question of whether alveolar lining fluid contained collectins beyond SP-A.","evidence":"Biochemical purification, 2D-PAGE, gel filtration, and peptide sequencing from rat type II cells","pmids":["2675969"],"confidence":"High","gaps":["Full quaternary structure not yet determined","Human homolog not yet cloned","Functional role unknown"]},{"year":1991,"claim":"Cloning of human SP-D cDNA established it as a C-type lectin with a conserved CRD containing calcium-dependent saccharide binding, placing it in the mannose-binding lectin family and predicting innate immune functions.","evidence":"cDNA library screening, DNA sequencing, immunoprecipitation of translation products, peptide antibody validation","pmids":["1898081"],"confidence":"High","gaps":["Ligand specificity of the CRD undefined","Structural basis of carbohydrate recognition unknown"]},{"year":1992,"claim":"Identification of glucosylceramide and phosphatidylinositol as specific SP-D ligands, together with ultrastructural localization showing distinct intracellular trafficking from SP-A, established that SP-D has unique lipid-binding specificity and a secretory pathway separate from lamellar body-associated surfactant components.","evidence":"TLC overlay, mass spectrometry, liposome reconstitution binding, immunogold EM with double-labeling in rat lung","pmids":["1530650","1457414","1527377"],"confidence":"High","gaps":["Physiological consequence of lipid binding unclear","No information on pathogen binding"]},{"year":1994,"claim":"Electron microscopy and hydrodynamic analysis revealed SP-D assembles as a cruciform dodecamer of four trimeric arms, each 46 nm long, explaining how multivalent CRD presentation enables high-avidity pathogen recognition including influenza A virus aggregation and enhanced neutrophil function.","evidence":"Freeze-dried EM, pepsin/collagenase digestion, hemagglutination inhibition, neutrophil binding and respiratory burst assays","pmids":["8006040","8040272"],"confidence":"High","gaps":["Atomic-resolution structure unavailable","Mechanism of neutrophil protection not defined at receptor level"]},{"year":1996,"claim":"Demonstration that higher-order multimers of dodecamers are several-fold more potent than dodecamers at viral aggregation and neutrophil protection established a valency-dependent model for SP-D innate immune function.","evidence":"Recombinant hSP-D in CHO cells fractionated by gel filtration; EM, hemagglutination inhibition, neutrophil protection assays","pmids":["8944718"],"confidence":"High","gaps":["Determinants of multimerization beyond dodecamer undefined","In vivo relevance of multimer vs. dodecamer not tested"]},{"year":2000,"claim":"SP-D knockout and transgenic rescue experiments demonstrated that SP-D locally regulates surfactant phospholipid pool size—loss causes 3–4-fold lipid accumulation and accelerated large-to-small aggregate conversion, both corrected by lung-specific SP-D re-expression—establishing SP-D as a non-redundant regulator of surfactant homeostasis.","evidence":"SP-D gene-targeted mice, SP-C promoter transgenic rescue, BAL phospholipid measurements, radiolabeled kinetics","pmids":["10956621","10666121"],"confidence":"High","gaps":["Molecular mechanism of lipid homeostasis regulation unclear","Whether SP-D acts on type II cells vs. macrophages not resolved"]},{"year":2001,"claim":"Dodecameric assembly via N-terminal Cys15/20 disulfide bonds was shown to be required for surfactant homeostasis and prevention of emphysema but dispensable for antiviral activity, dissecting oligomerization-dependent and -independent functions; epistasis with GM-CSF knockout revealed independent pathways for macrophage activation and lipid catabolism.","evidence":"Cys15/20Ser mutant transgene in SP-D null mice; SP-D/GM-CSF double knockout with BAL lipid, morphological, and stereological analysis","pmids":["11278637","11504698","11350793"],"confidence":"High","gaps":["Direct receptor or signaling target on macrophages for N-terminal/collagen domain not identified","Mechanism of emphysema development unresolved"]},{"year":2002,"claim":"Domain-swap chimeras and conditional induction/withdrawal experiments separated SP-D functions into collagen/N-terminal-dependent (macrophage regulation, emphysema prevention) and CRD-dependent (pathogen clearance, lipid regulation) modules, and showed emphysema is irreversible once established while surfactant homeostasis is rapidly correctable.","evidence":"SP-D/conglutinin chimeric transgene, doxycycline-regulated conditional transgene in SP-D null mice, CRD mutagenesis with Mycoplasma binding","pmids":["11956209","12163500","11916969"],"confidence":"High","gaps":["Specific signaling pathways downstream of collagen domain engagement unknown","Whether emphysema reflects a developmental window or ongoing tissue destruction not fully resolved"]},{"year":2002,"claim":"SP-D null mice display persistent pulmonary T cell activation with elevated CD4+/CD8+ activation markers and proinflammatory cytokines, establishing SP-D as a local immunoregulatory factor that suppresses adaptive immune activation in the lung.","evidence":"Flow cytometry of intrapulmonary lymphocytes from SP-D−/− mice, cytokine ELISA, RT-PCR","pmids":["12091242"],"confidence":"High","gaps":["Whether T cell suppression is direct or mediated via macrophage/dendritic cell regulation unknown","Human relevance not tested"]},{"year":2004,"claim":"Identification of NFATc3 as a transcriptional co-activator of Sftpd, synergizing with TTF-1, revealed a calcineurin-dependent regulatory pathway for SP-D expression in lung epithelium.","evidence":"Promoter-reporter assays, gel shift, DNase I footprinting, calcineurin/cyclosporin inhibition, co-immunoprecipitation","pmids":["15173172"],"confidence":"High","gaps":["Upstream signals activating calcineurin/NFATc3 in type II cells not identified","Relevance of this pathway to disease-associated SP-D deficiency unknown"]},{"year":2005,"claim":"The common Met11Thr polymorphism was shown to alter SP-D oligomerization: Thr11 lacks the highest-order multimers and preferentially binds isolated LPS over intact organisms, providing a structural basis for genetic variation in innate immune function.","evidence":"Genotyping, gel filtration, AFM of purified protein, ELISA, mannan/virus binding assays","pmids":["15661913"],"confidence":"High","gaps":["Clinical outcomes associated with Met11Thr not mechanistically dissected","Whether Thr11 affects surfactant homeostasis not tested"]},{"year":2006,"claim":"Crystallographic and mutagenesis studies identified Phe335 as a critical CRD residue that stacks with terminal sugar rings to determine ligand specificity, while in vivo collagen-domain deletion confirmed that the collagen region is required for macrophage regulation and surfactant homeostasis but dispensable for innate immune pathogen clearance.","evidence":"Crystal structure of neck+CRD with ligands, Phe335 site-directed mutagenesis, collagen-deletion transgene in SP-D null mice","pmids":["16636058","16787926","16500946"],"confidence":"High","gaps":["Full-length dodecameric structure not solved","Whether Phe335 variants exist in human populations unknown"]},{"year":2009,"claim":"SP-D was found to bind SIRPα and SIRPβ via their D3 immunoglobulin domains in a calcium- and glycan-dependent manner at a site distinct from CD47, identifying a receptor pathway for SP-D signaling on myeloid cells.","evidence":"Domain-deleted SIRPα/SIRPβ binding assays, N-glycosylation site mutagenesis, binding to neutrophil surface SIRPα","pmids":["22511785"],"confidence":"High","gaps":["Downstream signaling consequences of SP-D–SIRPα interaction not characterized","Whether SIRPα mediates SP-D's anti-inflammatory functions in vivo not tested"]},{"year":2018,"claim":"S-nitrosylation of SP-D was identified as a post-translational modification that disrupts oligomerization and abolishes eosinophil DNA trap inhibition, linking oxidative/nitrosative stress to loss of SP-D immune-regulatory function in conditions like asthma; AFM quantification established dodecamers as the predominant assembly form stabilized by N-terminal non-covalent interactions.","evidence":"AFM of recombinant and patient-derived SP-D, in vitro S-nitrosylation, eosinophil trap assays, Sftpd−/− mice with allergen/ozone challenge","pmids":["29626540","29733456"],"confidence":"High","gaps":["Identity of S-nitrosylated cysteine residues not mapped","Whether S-nitrosylation occurs in vivo at sufficient stoichiometry to regulate function not quantified"]},{"year":2019,"claim":"SP-D was shown to attenuate LPS-induced NETosis and to rescue surfactant biophysical function from NET-mediated inhibition, establishing a protective feedback loop wherein SP-D prevents NET-induced surfactant dysfunction during inflammation.","evidence":"Human neutrophil NETosis assay, Sftpd−/− mouse LPS model, surface activity measurements of surfactant with/without NETs and SP-D","pmids":["31872075"],"confidence":"High","gaps":["Receptor on neutrophils mediating SP-D NETosis suppression not identified","Whether NET inhibition operates through SIRPα or another pathway unknown"]},{"year":null,"claim":"Key unresolved questions include the signaling pathways downstream of SP-D–SIRPα engagement on macrophages and neutrophils, the molecular mechanism by which SP-D regulates surfactant lipid pool size (direct type II cell vs. macrophage-mediated), the full-length dodecameric atomic structure, and whether S-nitrosylation site identity and stoichiometry explain disease-associated SP-D dysfunction.","evidence":"","pmids":[],"confidence":"Low","gaps":["No atomic structure of full-length SP-D dodecamer","Signaling downstream of SIRPα/β engagement uncharacterized","Direct vs. macrophage-mediated regulation of surfactant homeostasis unresolved","In vivo relevance of S-nitrosylation stoichiometry not quantified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[5,6,17]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[10,12,27]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[13,14,31]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,3,8,13]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[4]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[9,10,11,17,27,29,31]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[5,6,13,14]}],"complexes":[],"partners":["SPA","SIRPA","SIRPB","NFATC3","NKX2-1","MMP9"],"other_free_text":[]},"mechanistic_narrative":"SP-D (SFTPD) is a collagen-containing C-type lectin collectin that assembles as disulfide-stabilized trimers, dodecamers, and higher-order multimers to regulate pulmonary surfactant phospholipid homeostasis and innate immune defense in the lung. The N-terminal and collagen domains govern oligomerization and are required for macrophage regulation and surfactant lipid homeostasis, while the homotrimeric carbohydrate recognition domain (CRD) mediates calcium-dependent binding to glucosylceramide, phosphatidylinositol, bacterial membrane lipids, and viral hemagglutinin—enabling pathogen aggregation, neutrophil and monocyte chemoattraction, NETosis suppression, and engagement of SIRPα/SIRPβ receptors [PMID:8006040, PMID:8040272, PMID:10956621, PMID:11278637, PMID:16636058, PMID:22511785, PMID:31872075]. Transcription of SFTPD is co-activated by NFATc3 in complex with TTF-1, and post-translational S-nitrosylation disrupts oligomerization and abrogates immune-regulatory functions including inhibition of eosinophil extracellular DNA trap formation [PMID:15173172, PMID:29733456]. SP-D deficiency in mice causes surfactant lipid accumulation, foamy macrophage infiltration, progressive emphysema, and dysregulated pulmonary T cell activation, with surfactant homeostasis correctable by lung-specific SP-D re-expression but emphysema being irreversible once established [PMID:10956621, PMID:12091242, PMID:12163500]."},"prefetch_data":{"uniprot":{"accession":"P35247","full_name":"Pulmonary surfactant-associated protein D","aliases":["Collectin-7","Lung surfactant protein D"],"length_aa":375,"mass_kda":37.7,"function":"Contributes to the lung's defense against inhaled microorganisms, organic antigens and toxins. Interacts with compounds such as bacterial lipopolysaccharides, oligosaccharides and fatty acids and modulates leukocyte action in immune response. May participate in the extracellular reorganization or turnover of pulmonary surfactant. Binds strongly maltose residues and to a lesser extent other alpha-glucosyl moieties","subcellular_location":"Secreted, extracellular space, extracellular matrix; Secreted, extracellular space, surface film","url":"https://www.uniprot.org/uniprotkb/P35247/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SFTPD","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SFTPD","total_profiled":1310},"omim":[{"mim_id":"619611","title":"INTERSTITIAL LUNG DISEASE 1; ILD1","url":"https://www.omim.org/entry/619611"},{"mim_id":"606862","title":"OSTEOCLAST-ASSOCIATED RECEPTOR; OSCAR","url":"https://www.omim.org/entry/606862"},{"mim_id":"601969","title":"DELETED IN MALIGNANT BRAIN TUMORS 1; DMBT1","url":"https://www.omim.org/entry/601969"},{"mim_id":"300770","title":"SURFACTANT METABOLISM DYSFUNCTION, PULMONARY, 4; SMDP4","url":"https://www.omim.org/entry/300770"},{"mim_id":"178640","title":"SURFACTANT, PULMONARY-ASSOCIATED PROTEIN B; SFTPB","url":"https://www.omim.org/entry/178640"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lung","ntpm":479.1}],"url":"https://www.proteinatlas.org/search/SFTPD"},"hgnc":{"alias_symbol":["SP-D","COLEC7"],"prev_symbol":["SFTP4"]},"alphafold":{"accession":"P35247","domains":[{"cath_id":"3.10.100.10","chopping":"262-375","consensus_level":"high","plddt":98.0165,"start":262,"end":375}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P35247","model_url":"https://alphafold.ebi.ac.uk/files/AF-P35247-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P35247-F1-predicted_aligned_error_v6.png","plddt_mean":65.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SFTPD","jax_strain_url":"https://www.jax.org/strain/search?query=SFTPD"},"sequence":{"accession":"P35247","fasta_url":"https://rest.uniprot.org/uniprotkb/P35247.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P35247/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P35247"}},"corpus_meta":[{"pmid":"16213021","id":"PMC_16213021","title":"Surfactant 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the CRD contains conserved cysteine residues and shows high homology with mannose-binding subfamily C-type lectins.\",\n      \"method\": \"cDNA library screening, DNA sequencing, immunoprecipitation, synthetic peptide antibodies, amino-terminal microsequencing\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct CRD identification via sequencing and functional antibody validation\",\n      \"pmids\": [\"1898081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Native 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 to type II cells; this activity requires SP-D-associated lipids and involves direct SP-D–SP-A interaction.\",\n      \"method\": \"Primary type II cell secretion assay, radiolabeled SP-A competition binding, nitrocellulose overlay, butanol extraction of SP-D\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional assays in primary cells; single lab\",\n      \"pmids\": [\"1930130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"SP-D mRNA and protein first appear in rat lung at gestational day 21 in cuboidal epithelial cells lining immature airspaces, and in adult lung in type II and nonciliated bronchiolar cells, with SP-D secreted into amniotic fluid, establishing developmental expression pattern.\",\n      \"method\": \"Northern hybridization, immunoperoxidase staining, cell-free translation, affinity chromatography\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization with functional correlation to developmental timing\",\n      \"pmids\": [\"1878250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"SP-D localizes in type II cells (endoplasmic reticulum, Golgi, multivesicular bodies but not lamellar bodies), Clara cells (secretory granules at apical domain), and alveolar macrophages (endocytotic structures); in Clara cells SP-D co-localizes with SP-A in the same granules but is confined to the periphery while SP-A distributes throughout.\",\n      \"method\": \"Immunogold electron microscopy, double-labeling with anti-SP-A and lysosomal markers, BSAG endocytotic pathway tracing\",\n      \"journal\": \"Journal of histochemistry and cytochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ultrastructural localization with multiple controls and double-labeling\",\n      \"pmids\": [\"1527377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"SP-D binds exclusively to glucosylceramide (GlcCer) among glycolipids tested, in a calcium-dependent and antibody-inhibitable manner; Mg2+ cannot substitute for Ca2+.\",\n      \"method\": \"TLC overlay with 125I-labeled SP-D, competition assay, antibody inhibition\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct ligand binding with specific controls; single lab\",\n      \"pmids\": [\"1530650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"SP-D binds phosphatidylinositol (PI) as its major glycolipid ligand in surfactant in a calcium-dependent, saccharide-inhibitable manner, including binding to PI in lipid bilayer liposomes.\",\n      \"method\": \"2D-TLC overlay with 125I-SP-D, affinity purification, mass spectrometry, Percoll density gradient liposome binding\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — ligand identified by multiple methods including mass spectrometry and reconstituted bilayer assay\",\n      \"pmids\": [\"1457414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"SP-D is encoded on chromosome 10q22.2-23.1; the collagen domain is encoded on five exons including four tandem 117-bp exons, while the signal peptide/N-terminal domain, CRD, and linking sequence are each on a single exon, consistent with modular evolution.\",\n      \"method\": \"Genomic clone characterization, sequencing, segregation analysis with HindIII, fluorescence in situ hybridization, PCR with somatic cell hybrids\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct genomic sequencing and FISH mapping\",\n      \"pmids\": [\"8428971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"SP-D forms a dodecameric quaternary structure assembled as homopolymers of four identical trimeric subunits, each arm 46 nm long with a globular CRD terminal expansion; interchain disulfide bonds at the N-terminal domain stabilize trimer interactions, and higher-order multimeric assemblies also occur.\",\n      \"method\": \"Electron microscopy (freeze-dried), hydrodynamic analysis, pepsin digestion, sulfhydryl reduction, bacterial collagenase digestion\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structural determination by EM and biochemical dissection; foundational paper\",\n      \"pmids\": [\"8006040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"SP-D potently inhibits influenza A virus (IAV) hemagglutination and causes viral aggregation via its calcium-dependent carbohydrate-binding CRD; SP-D enhances neutrophil binding of IAV and respiratory burst, and diminishes neutrophil dysfunction caused by IAV.\",\n      \"method\": \"Hemagglutination inhibition assay, viral aggregation assay, neutrophil binding assay, respiratory burst measurement, calcium/saccharide inhibition controls\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional assays with mechanistic controls; replicated with human, rat and recombinant SP-D\",\n      \"pmids\": [\"8040272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"SP-D acts as a chemoattractant for human neutrophils and monocytes in a dose-dependent, saccharide-inhibitable (maltose-sensitive) manner via interactions involving the carboxy-terminal lectin domain.\",\n      \"method\": \"Modified Boyden chamber chemotaxis assay, checkerboard analysis, antibody and sugar inhibition\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct functional assay with domain-specific antibody and sugar inhibition\",\n      \"pmids\": [\"7695920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Higher-order multimers of human SP-D (multimers of dodecamers) are several-fold more potent than dodecamers at causing IAV aggregation and protecting neutrophils from IAV deactivation, demonstrating valency-dependent CRD interactions; the propensity to form multimers is determined by primary structure.\",\n      \"method\": \"Recombinant hSP-D expression in CHO cells, gel filtration, electron microscopy, hemagglutination inhibition, neutrophil protection assay\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structure-function with recombinant protein fractionation; multiple assays\",\n      \"pmids\": [\"8944718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The trimeric carbohydrate recognition domain (CRD) of SP-D is sufficient for chemotactic activity toward neutrophils, with peak activity at 10^-10 M; activity is abolished by 20 mM maltose, indicating CRD-dependent recognition.\",\n      \"method\": \"Recombinant neck+CRD expression in E. coli, gel-filtration characterization, Boyden chamber chemotaxis, maltose inhibition\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain-specific recombinant protein with sugar inhibition; single lab\",\n      \"pmids\": [\"9887065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"SP-D deficiency causes a 3-4 fold increase in alveolar surfactant lipids associated with accelerated conversion of large- to small-aggregate surfactant; pulmonary-specific transgenic re-expression of SP-D corrects the lipid accumulation, demonstrating that SP-D acts locally to regulate surfactant phospholipid homeostasis.\",\n      \"method\": \"SP-D gene-targeted mice, SP-C promoter-driven transgene, bronchoalveolar lavage phospholipid measurements, radiolabeled phospholipid kinetics\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic rescue experiment with quantitative metabolic readouts; two complementary papers\",\n      \"pmids\": [\"10956621\", \"10666121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Dodecameric (disulfide cross-linked oligomeric) assembly of SP-D is required for regulation of surfactant phospholipid homeostasis and prevention of emphysema and foamy macrophages in vivo; trimeric SP-D (Cys15/20 → Ser mutant) fails to rescue these phenotypes but does not affect antiviral activity.\",\n      \"method\": \"Transgenic mice expressing Cys15/20Ser mutant rSP-D in SP-D null background, bronchoalveolar lavage lipid and morphological analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo domain/mutagenesis dissection with clear phenotypic readouts\",\n      \"pmids\": [\"11278637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SP-D and GM-CSF regulate surfactant homeostasis by distinct mechanisms: double-knockout mice show approximately additive phospholipid accumulation, and GM-CSF expression corrects GM-CSF-dependent catabolism defects but not SP-D-null lung pathology.\",\n      \"method\": \"SP-D/GM-CSF double knockout mice, GM-CSF lung-selective transgene rescue, saturated phosphatidylcholine pool size measurements\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis by double knockout plus transgenic rescue; independent pathways established\",\n      \"pmids\": [\"11504698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"GM-CSF mediates alveolar macrophage proliferation and type II cell hypertrophy in SP-D null mice; double null SP-D/GM-CSF mice show large but not foamy macrophages and mostly normal type II cells, while emphysema persists, separating GM-CSF-dependent from GM-CSF-independent SP-D functions.\",\n      \"method\": \"SP-D/GM-CSF double knockout breeding, BAL analysis, electron and light microscopy\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis double knockout with multiple cellular readouts\",\n      \"pmids\": [\"11350793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Human SP-D binds Mycoplasma pneumoniae via calcium-dependent, carbohydrate-recognition-domain-mediated interactions with bacterial membrane lipids (not proteins); a CRD tandem mutant (E321Q/N323D) abolishes binding, directly implicating the CRD.\",\n      \"method\": \"Ca2+/EGTA-dependent binding assays, protease pre-treatment of membranes, 2D-TLC overlay, CRD mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — active-site mutagenesis with reconstituted binding assay\",\n      \"pmids\": [\"11916969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Restoring SP-D expression in adult SP-D null mice via doxycycline-regulated transgene corrects surfactant lipid abnormalities and alveolar macrophage phenotype within days, but established emphysema is not reversed; loss of SP-D in corrected adults causes focal emphysema but not phospholipid abnormalities, showing these pathways are separable.\",\n      \"method\": \"Conditional doxycycline-regulated transgene in SP-D null mice, BAL lipid assays, morphometric analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reversibility experiment separates mechanistic pathways\",\n      \"pmids\": [\"12163500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SP-D/conglutinin chimera (SP-D N-terminal/collagen + conglutinin neck+CRD) corrects surfactant phospholipid abnormalities and viral clearance defects in SP-D null mice but does not correct ongoing lung inflammation and emphysema, indicating distinct roles for CRD identity versus N-terminal domains in different SP-D functions.\",\n      \"method\": \"Chimeric transgene expression in SP-D null mice, BAL lipid assay, influenza A clearance assay, lung morphology\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain-swap chimera in vivo with multiple phenotypic endpoints\",\n      \"pmids\": [\"11956209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SP-D null mice develop persistent pulmonary T cell activation (increased CD4+ and CD8+ T cells expressing CD69 and CD25, elevated BAL CD4 lymphocytes, increased IL-12 and IL-6), demonstrating a local immunoregulatory role for SP-D in suppressing T cell responses in vivo.\",\n      \"method\": \"Flow cytometry of intrapulmonary lymphocytes from SP-D-/- mice, RNase protection assay, RT-PCR, ELISA for cytokines\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function mouse model with multiple immunological readouts\",\n      \"pmids\": [\"12091242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"NFATc3 regulates SP-D gene (Sftpd) transcription via an NFAT-dependent enhancer in the Sftpd promoter; NFATc3 and TTF-1 synergize, co-immunoprecipitate, and physically interact in vitro to activate Sftpd transcription in lung epithelial cells.\",\n      \"method\": \"Promoter-reporter assays, gel supershift/DNase I footprinting, calcineurin/cyclosporin/VIVIT inhibition, co-immunoprecipitation, in vitro protein interaction\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — transcriptional mechanism established by promoter assays, gel shift, co-IP, and in vitro interaction\",\n      \"pmids\": [\"15173172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"GM-CSF is required for type II cell hyperplasia and hypertrophy in SP-D-deficient mice but not for emphysema development; emphysema-like changes in SP-D null mice are independent of GM-CSF-dependent macrophage activity.\",\n      \"method\": \"SP-D/GM-CSF double knockout mice, design-based stereology at light and electron microscope levels\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis double knockout with quantitative stereological analysis\",\n      \"pmids\": [\"15310555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"A common SFTPD polymorphism at codon 11 (Met11Thr) influences SP-D oligomerization: Thr11 SP-D lacks the highest molecular weight multimeric form, has lower serum levels, and shows preferential binding to isolated LPS rather than intact bacteria/viruses, whereas Met11 multimers preferentially bind intact organisms.\",\n      \"method\": \"Genotyping, gel filtration, atomic force microscopy of purified protein, ELISA, mannan- and virus-binding assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — AFM structural analysis combined with functional binding assays and human genotype-phenotype correlation\",\n      \"pmids\": [\"15661913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The collagenous domain of SP-D is required for regulation of pulmonary macrophage activation, airspace remodeling, and surfactant lipid homeostasis in vivo, but is dispensable for assembly of disulfide-stabilized oligomers and for innate immune response to influenza A.\",\n      \"method\": \"Collagen deletion mutant SP-D transgene in wild-type and Sftpd-/- mice, BAL lipid assay, influenza A clearance, lung morphology, surfactant ultrastructure\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain deletion mutant in vivo with multiple phenotypic readouts\",\n      \"pmids\": [\"16787926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Phenylalanine 335 in the SP-D CRD mediates preferential binding to aromatic glycosides and maltotriose via ring-stacking interactions; Phe335Leu substitution reduces affinity for maltotriose and p-nitrophenyl-maltoside, and Phe335Ala abolishes mannan binding; crystallographic analysis shows stacking of the terminal glucose or nitrophenyl ring with the Phe335 aromatic ring.\",\n      \"method\": \"Site-directed mutagenesis, fluorescence polarization binding assay, crystallographic analysis of neck+CRD with ligands\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus mutagenesis confirming mechanism\",\n      \"pmids\": [\"16636058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Neither full-length SP-A nor chimeric NH2-SP-A/SP-D (SP-A N-terminal+collagen fused to SP-D neck+CRD) can substitute for SP-D in correcting emphysema, foamy macrophages, or lipid accumulation in SP-D null mice; SP-D N-terminal and collagen domains are required for proper oligomerization and surfactant lipid association.\",\n      \"method\": \"Transgenic expression of chimeric proteins in Sftpd-/- mice, BAL lipid/protein assays, lung morphology\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain-swap chimera in vivo; multiple null controls\",\n      \"pmids\": [\"16500946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SP-D binds to the membrane-proximal immunoglobulin-like domain (D3) of SIRPα in a calcium- and carbohydrate-dependent manner via specific N-glycosylated residues on D3; SP-D also binds the analogous D3 domain of SIRPβ; the SP-D binding site on SIRPα is distinct from the CD47 binding site on D1.\",\n      \"method\": \"Domain-deleted SIRPα/SIRPβ mutant binding assays, N-glycosylation site mutagenesis, binding to SIRPα on human neutrophils and differentiated neutrophil-like cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain deletion and glycosylation mutagenesis with cell surface binding validation\",\n      \"pmids\": [\"22511785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MMP-9 cleaves SP-D in vitro, abolishing its ability to aggregate bacteria and enhance phagocytosis by alveolar macrophages, while preserving LPS binding; MMP-9 cleaves SP-D more efficiently than neutrophil elastase at physiological calcium concentrations.\",\n      \"method\": \"In vitro protease cleavage assay, bacterial aggregation assay, macrophage phagocytosis assay, solid-phase LPS binding\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional readouts; in vitro only\",\n      \"pmids\": [\"22860023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SP-D directly binds to eosinophil membranes in a concentration- and carbohydrate-dependent manner and inhibits eosinophil extracellular DNA trap formation; S-nitrosylation of SP-D (mimicking iNOS/oxidative conditions in asthma) causes de-oligomerization of SP-D and abolishes its ability to inhibit DNA trap formation.\",\n      \"method\": \"Confocal imaging with recombinant SP-D, murine and human eosinophil assays, iNOS inhibition, S-nitrosylation in vitro, Sftpd-/- mice with allergen/ozone challenge\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct binding shown by imaging, mechanistic PTM (S-nitrosylation) established in vitro and in vivo\",\n      \"pmids\": [\"29733456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Dodecamers are the predominant SP-D oligomeric form (>50% by mass); dodecamer formation requires two hexamers as a minimal unit and is stabilized by non-covalent, ionic, and hydrophobic interactions between N-terminal domains and proximal collagen stems; acidic conditions promote compact dodecamer configuration.\",\n      \"method\": \"Atomic force microscopy (AFM) of recombinant and patient-derived hSP-D, electrophoresis, comparative analysis at different pH\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct structural analysis by AFM with quantitative assessment\",\n      \"pmids\": [\"29626540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SP-D attenuates LPS-mediated NETosis in human neutrophils by binding LPS; SP-D deficiency in mice leads to excess NET formation in lungs during LPS-mediated inflammation; NETs inhibit pulmonary surfactant biophysical function in the absence of SP-D, and SP-D reverses NET-mediated surfactant inhibition.\",\n      \"method\": \"Human neutrophil NETosis assay with recombinant SP-D, Sftpd-/- mouse LPS model, surfactant biophysical assay (surface activity measurement)\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vitro mechanism confirmed in vivo in knockout model with biophysical functional readout\",\n      \"pmids\": [\"31872075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"KGF increases SP-D mRNA and protein secretion in rat alveolar type II cells in primary culture at the air-liquid interface; TPA+terbutaline stimulates phosphatidylcholine and SP-A secretion but not SP-D, indicating SP-D secretion is regulated by a distinct pathway from SP-A.\",\n      \"method\": \"Primary rat type II cell culture, Northern blot, ELISA for SP-D protein in apical medium, [3H]PC secretion assay\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct secretion measurement with pharmacological dissection; single lab\",\n      \"pmids\": [\"9476903\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SP-D (SFTPD) is a collagen-containing C-type lectin collectin secreted by type II pneumocytes and Clara cells that assembles as disulfide-stabilized trimers, dodecamers, and higher-order multimers; its N-terminal/collagen domains govern oligomerization and surfactant phospholipid homeostasis (via locally regulating alveolar macrophage function), while its homotrimeric carbohydrate recognition domain (CRD), with Phe335 as a critical stacking residue, mediates calcium-dependent binding to glucosylceramide, phosphatidylinositol, bacterial lipids, and viral hemagglutinin—enabling pathogen aggregation, neutrophil and monocyte chemoattraction, NETosis suppression, and SIRPα/SIRPβ receptor engagement—and its transcription is co-activated by NFATc3 in complex with TTF-1; post-translational S-nitrosylation disrupts oligomerization and abrogates immune-regulatory function, and cleavage by MMP-9 destroys bactericidal activities while preserving LPS binding.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SP-D (SFTPD) is a collagen-containing C-type lectin collectin that assembles as disulfide-stabilized trimers, dodecamers, and higher-order multimers to regulate pulmonary surfactant phospholipid homeostasis and innate immune defense in the lung. The N-terminal and collagen domains govern oligomerization and are required for macrophage regulation and surfactant lipid homeostasis, while the homotrimeric carbohydrate recognition domain (CRD) mediates calcium-dependent binding to glucosylceramide, phosphatidylinositol, bacterial membrane lipids, and viral hemagglutinin—enabling pathogen aggregation, neutrophil and monocyte chemoattraction, NETosis suppression, and engagement of SIRPα/SIRPβ receptors [PMID:8006040, PMID:8040272, PMID:10956621, PMID:11278637, PMID:16636058, PMID:22511785, PMID:31872075]. Transcription of SFTPD is co-activated by NFATc3 in complex with TTF-1, and post-translational S-nitrosylation disrupts oligomerization and abrogates immune-regulatory functions including inhibition of eosinophil extracellular DNA trap formation [PMID:15173172, PMID:29733456]. SP-D deficiency in mice causes surfactant lipid accumulation, foamy macrophage infiltration, progressive emphysema, and dysregulated pulmonary T cell activation, with surfactant homeostasis correctable by lung-specific SP-D re-expression but emphysema being irreversible once established [PMID:10956621, PMID:12091242, PMID:12163500].\",\n  \"teleology\": [\n    {\n      \"year\": 1989,\n      \"claim\": \"Identification of SP-D as a distinct collagenous surfactant glycoprotein that forms disulfide-bonded trimers of 43 kDa subunits resolved the question of whether alveolar lining fluid contained collectins beyond SP-A.\",\n      \"evidence\": \"Biochemical purification, 2D-PAGE, gel filtration, and peptide sequencing from rat type II cells\",\n      \"pmids\": [\"2675969\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full quaternary structure not yet determined\", \"Human homolog not yet cloned\", \"Functional role unknown\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Cloning of human SP-D cDNA established it as a C-type lectin with a conserved CRD containing calcium-dependent saccharide binding, placing it in the mannose-binding lectin family and predicting innate immune functions.\",\n      \"evidence\": \"cDNA library screening, DNA sequencing, immunoprecipitation of translation products, peptide antibody validation\",\n      \"pmids\": [\"1898081\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ligand specificity of the CRD undefined\", \"Structural basis of carbohydrate recognition unknown\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Identification of glucosylceramide and phosphatidylinositol as specific SP-D ligands, together with ultrastructural localization showing distinct intracellular trafficking from SP-A, established that SP-D has unique lipid-binding specificity and a secretory pathway separate from lamellar body-associated surfactant components.\",\n      \"evidence\": \"TLC overlay, mass spectrometry, liposome reconstitution binding, immunogold EM with double-labeling in rat lung\",\n      \"pmids\": [\"1530650\", \"1457414\", \"1527377\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological consequence of lipid binding unclear\", \"No information on pathogen binding\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Electron microscopy and hydrodynamic analysis revealed SP-D assembles as a cruciform dodecamer of four trimeric arms, each 46 nm long, explaining how multivalent CRD presentation enables high-avidity pathogen recognition including influenza A virus aggregation and enhanced neutrophil function.\",\n      \"evidence\": \"Freeze-dried EM, pepsin/collagenase digestion, hemagglutination inhibition, neutrophil binding and respiratory burst assays\",\n      \"pmids\": [\"8006040\", \"8040272\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution structure unavailable\", \"Mechanism of neutrophil protection not defined at receptor level\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Demonstration that higher-order multimers of dodecamers are several-fold more potent than dodecamers at viral aggregation and neutrophil protection established a valency-dependent model for SP-D innate immune function.\",\n      \"evidence\": \"Recombinant hSP-D in CHO cells fractionated by gel filtration; EM, hemagglutination inhibition, neutrophil protection assays\",\n      \"pmids\": [\"8944718\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of multimerization beyond dodecamer undefined\", \"In vivo relevance of multimer vs. dodecamer not tested\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"SP-D knockout and transgenic rescue experiments demonstrated that SP-D locally regulates surfactant phospholipid pool size—loss causes 3–4-fold lipid accumulation and accelerated large-to-small aggregate conversion, both corrected by lung-specific SP-D re-expression—establishing SP-D as a non-redundant regulator of surfactant homeostasis.\",\n      \"evidence\": \"SP-D gene-targeted mice, SP-C promoter transgenic rescue, BAL phospholipid measurements, radiolabeled kinetics\",\n      \"pmids\": [\"10956621\", \"10666121\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of lipid homeostasis regulation unclear\", \"Whether SP-D acts on type II cells vs. macrophages not resolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Dodecameric assembly via N-terminal Cys15/20 disulfide bonds was shown to be required for surfactant homeostasis and prevention of emphysema but dispensable for antiviral activity, dissecting oligomerization-dependent and -independent functions; epistasis with GM-CSF knockout revealed independent pathways for macrophage activation and lipid catabolism.\",\n      \"evidence\": \"Cys15/20Ser mutant transgene in SP-D null mice; SP-D/GM-CSF double knockout with BAL lipid, morphological, and stereological analysis\",\n      \"pmids\": [\"11278637\", \"11504698\", \"11350793\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct receptor or signaling target on macrophages for N-terminal/collagen domain not identified\", \"Mechanism of emphysema development unresolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Domain-swap chimeras and conditional induction/withdrawal experiments separated SP-D functions into collagen/N-terminal-dependent (macrophage regulation, emphysema prevention) and CRD-dependent (pathogen clearance, lipid regulation) modules, and showed emphysema is irreversible once established while surfactant homeostasis is rapidly correctable.\",\n      \"evidence\": \"SP-D/conglutinin chimeric transgene, doxycycline-regulated conditional transgene in SP-D null mice, CRD mutagenesis with Mycoplasma binding\",\n      \"pmids\": [\"11956209\", \"12163500\", \"11916969\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific signaling pathways downstream of collagen domain engagement unknown\", \"Whether emphysema reflects a developmental window or ongoing tissue destruction not fully resolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"SP-D null mice display persistent pulmonary T cell activation with elevated CD4+/CD8+ activation markers and proinflammatory cytokines, establishing SP-D as a local immunoregulatory factor that suppresses adaptive immune activation in the lung.\",\n      \"evidence\": \"Flow cytometry of intrapulmonary lymphocytes from SP-D−/− mice, cytokine ELISA, RT-PCR\",\n      \"pmids\": [\"12091242\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether T cell suppression is direct or mediated via macrophage/dendritic cell regulation unknown\", \"Human relevance not tested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identification of NFATc3 as a transcriptional co-activator of Sftpd, synergizing with TTF-1, revealed a calcineurin-dependent regulatory pathway for SP-D expression in lung epithelium.\",\n      \"evidence\": \"Promoter-reporter assays, gel shift, DNase I footprinting, calcineurin/cyclosporin inhibition, co-immunoprecipitation\",\n      \"pmids\": [\"15173172\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals activating calcineurin/NFATc3 in type II cells not identified\", \"Relevance of this pathway to disease-associated SP-D deficiency unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"The common Met11Thr polymorphism was shown to alter SP-D oligomerization: Thr11 lacks the highest-order multimers and preferentially binds isolated LPS over intact organisms, providing a structural basis for genetic variation in innate immune function.\",\n      \"evidence\": \"Genotyping, gel filtration, AFM of purified protein, ELISA, mannan/virus binding assays\",\n      \"pmids\": [\"15661913\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Clinical outcomes associated with Met11Thr not mechanistically dissected\", \"Whether Thr11 affects surfactant homeostasis not tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Crystallographic and mutagenesis studies identified Phe335 as a critical CRD residue that stacks with terminal sugar rings to determine ligand specificity, while in vivo collagen-domain deletion confirmed that the collagen region is required for macrophage regulation and surfactant homeostasis but dispensable for innate immune pathogen clearance.\",\n      \"evidence\": \"Crystal structure of neck+CRD with ligands, Phe335 site-directed mutagenesis, collagen-deletion transgene in SP-D null mice\",\n      \"pmids\": [\"16636058\", \"16787926\", \"16500946\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length dodecameric structure not solved\", \"Whether Phe335 variants exist in human populations unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"SP-D was found to bind SIRPα and SIRPβ via their D3 immunoglobulin domains in a calcium- and glycan-dependent manner at a site distinct from CD47, identifying a receptor pathway for SP-D signaling on myeloid cells.\",\n      \"evidence\": \"Domain-deleted SIRPα/SIRPβ binding assays, N-glycosylation site mutagenesis, binding to neutrophil surface SIRPα\",\n      \"pmids\": [\"22511785\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling consequences of SP-D–SIRPα interaction not characterized\", \"Whether SIRPα mediates SP-D's anti-inflammatory functions in vivo not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"S-nitrosylation of SP-D was identified as a post-translational modification that disrupts oligomerization and abolishes eosinophil DNA trap inhibition, linking oxidative/nitrosative stress to loss of SP-D immune-regulatory function in conditions like asthma; AFM quantification established dodecamers as the predominant assembly form stabilized by N-terminal non-covalent interactions.\",\n      \"evidence\": \"AFM of recombinant and patient-derived SP-D, in vitro S-nitrosylation, eosinophil trap assays, Sftpd−/− mice with allergen/ozone challenge\",\n      \"pmids\": [\"29626540\", \"29733456\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of S-nitrosylated cysteine residues not mapped\", \"Whether S-nitrosylation occurs in vivo at sufficient stoichiometry to regulate function not quantified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"SP-D was shown to attenuate LPS-induced NETosis and to rescue surfactant biophysical function from NET-mediated inhibition, establishing a protective feedback loop wherein SP-D prevents NET-induced surfactant dysfunction during inflammation.\",\n      \"evidence\": \"Human neutrophil NETosis assay, Sftpd−/− mouse LPS model, surface activity measurements of surfactant with/without NETs and SP-D\",\n      \"pmids\": [\"31872075\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor on neutrophils mediating SP-D NETosis suppression not identified\", \"Whether NET inhibition operates through SIRPα or another pathway unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the signaling pathways downstream of SP-D–SIRPα engagement on macrophages and neutrophils, the molecular mechanism by which SP-D regulates surfactant lipid pool size (direct type II cell vs. macrophage-mediated), the full-length dodecameric atomic structure, and whether S-nitrosylation site identity and stoichiometry explain disease-associated SP-D dysfunction.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No atomic structure of full-length SP-D dodecamer\", \"Signaling downstream of SIRPα/β engagement uncharacterized\", \"Direct vs. macrophage-mediated regulation of surfactant homeostasis unresolved\", \"In vivo relevance of S-nitrosylation stoichiometry not quantified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [5, 6, 17]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [10, 12, 27]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [13, 14, 31]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 3, 8, 13]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [9, 10, 11, 17, 27, 29, 31]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [5, 6, 13, 14]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"SPA\",\n      \"SIRPA\",\n      \"SIRPB\",\n      \"NFATc3\",\n      \"NKX2-1\",\n      \"MMP9\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}