{"gene":"SFTPA1","run_date":"2026-06-10T07:46:31","timeline":{"discoveries":[{"year":1991,"finding":"SP-A specifically and strongly binds dipalmitoylphosphatidylcholine (DPPC) in a calcium-dependent manner; binding requires the intact collagenous domain but not the oligosaccharide moiety; the nonpolar diacylglycerol group and the specific polar head group (phosphocholine) are both required; deglycosylated SP-A retains binding but the collagenase-resistant collagenous fragment does not.","method":"125I-SP-A thin-layer chromatogram overlay binding assay, EGTA inhibition, phospholipase C/A2 treatments, competitive inhibition with deglycosylated and collagenase-resistant SP-A fragments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro binding assay with multiple domain-deletion and chemical variants, replicated across multiple lipid species and conditions in a single rigorous study","pmids":["1993679"],"is_preprint":false},{"year":1989,"finding":"SP-A forms large oligomers dependent on an intact collagen-like domain; the cysteines in the non-collagen domain form intrachain disulfide bonds (between residues 135–226 and 204–218); the protein has a collagen-like triple helix and exhibits calcium-dependent aggregation at physiological calcium concentrations.","method":"Collagenase digestion, circular dichroism spectroscopy, thermal denaturation, disulfide bond mapping","journal":"The American journal of physiology","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural characterization by multiple orthogonal biochemical methods (CD, collagenase digestion, thermal stability) in a single rigorous study","pmids":["2610270"],"is_preprint":false},{"year":1990,"finding":"Each SP-A monomer binds two to three calcium ions; the higher-affinity calcium-binding site is located in the C-terminal carbohydrate recognition domain (CRD); calcium binding to this domain causes a conformational change and promotes reversible protein aggregation relevant to tubular myelin formation.","method":"Equilibrium dialysis, gel permeation chromatography, limited proteolysis fragment studies, intrinsic fluorescence spectroscopy","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro binding measurements with domain-specific fragment validation and multiple orthogonal methods in one study","pmids":["2271565"],"is_preprint":false},{"year":1988,"finding":"The hydroxylation of the collagenous domain of SP-A is required for its intracellular transport to the lamellar body fraction and secretion; disruption of triple-helix formation (by alpha,alpha'-dipyridyl or cis-4-hydroxy-L-proline) causes accumulation of high-mannose precursors intracellularly without secretion; carbohydrate processing (sialylation) is also dependent on an intact collagenous domain.","method":"Metabolic labeling of type II cells, inhibitor treatment, subcellular fractionation, endoglycosidase H resistance assay","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in primary type II cells with specific chemical inhibitors and biochemical fractionation, multiple orthogonal endpoints","pmids":["3355864"],"is_preprint":false},{"year":1989,"finding":"After intratracheal instillation, both SP-A protein and surfactant lipids are taken up by lung cells and incorporated into lamellar body-enriched secretory granules in a time-dependent manner, consistent with receptor-mediated recycling.","method":"Intratracheal instillation of radiolabeled lipid-SP-A complex, subcellular fractionation on discontinuous sucrose density gradients","journal":"Journal of applied physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo subcellular fractionation with dual radiolabels, single lab","pmids":["2708254"],"is_preprint":false},{"year":1989,"finding":"SP-A enhances the surface activity of lipid extract surfactant by improving the rate of phospholipid adsorption and spreading at the air-liquid interface, resulting in stable lipid monolayer formation at lower phospholipid and calcium concentrations.","method":"Pulsating bubble surfactometer assay of lipid extract surfactant reconstituted with purified SP-A","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro functional reconstitution assay, single lab, single method","pmids":["2713385"],"is_preprint":false},{"year":1991,"finding":"SP-A interacts with alveolar macrophages via a specific, mannose-dependent receptor distinct from the classical mannose receptor; binding and uptake occur via coated pits/vesicles and material is transported to secondary lysosomes; excess SP-A competitively inhibits uptake.","method":"Electron microscopy of SP-A-coated gold particles incubated with rat alveolar macrophages, competitive inhibition with mannan-BSA/galactosyl-BSA, mannose receptor down-regulation experiments","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — electron microscopy with gold-labeled ligand, competitive inhibition, receptor specificity controls; single lab","pmids":["1846339"],"is_preprint":false},{"year":1989,"finding":"SP-A uptake by macrophages and monocytes is mannose-dependent; the interaction is mediated at least in part by SP-A binding to mannose residues on the macrophage surface (not solely via the mannose receptor), as monocytes lacking mannose receptor activity still internalize SP-A gold particles in a mannose-dependent manner.","method":"Electron microscopy of SP-A-coated gold particles with human macrophages/monocytes, competitive inhibition with mannosyl-BSA vs galactosyl-BSA, ConA labeling of cell surface","journal":"European journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — electron microscopy with receptor-specificity controls, monocyte vs macrophage comparison; single lab","pmids":["2627938"],"is_preprint":false},{"year":1992,"finding":"SP-A enhances serum-independent phagocytosis of several bacterial species (E. coli, P. aeruginosa, S. aureus) by alveolar macrophages in a concentration-dependent manner; the effect is species- and growth-phase-dependent; more complex oligomeric SP-A is most effective.","method":"Phagocytosis assay of non-opsonized bacteria with purified SP-A variants (recombinant human SP-A1, SP-A2, and proteinosis-derived SP-A) and isolated alveolar macrophages","journal":"European journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct phagocytosis assay with multiple SP-A forms and bacterial species; single lab","pmids":["1639094"],"is_preprint":false},{"year":1993,"finding":"SP-A is internalized by alveolar type II cells via the endosomal system (including multivesicular bodies) into lamellar bodies; internalization is receptor-mediated (inhibited by excess unlabeled SP-A and by alkylation); cell shape/cytoskeletal organization regulates SP-A recycling efficiency.","method":"Electron microscopy of SP-A-colloidal gold conjugates in primary rat type II cells, competitive inhibition, fluid-phase marker co-internalization","journal":"The journal of histochemistry and cytochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct electron microscopy with gold conjugates and receptor-specificity controls; single lab","pmids":["8417113"],"is_preprint":false},{"year":1996,"finding":"A null mutation of the murine SP-A gene eliminates tubular myelin formation in the lung without altering postnatal survival, lung morphology, surfactant phospholipid pool sizes, SP-B/C/D levels, or lung compliance; SP-A is specifically required for tubular myelin assembly.","method":"Homologous recombination gene targeting in mice (SP-A -/- knockout), electron microscopy, lung function measurements, lipid analysis, Northern/Western blot","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic knockout with multiple orthogonal phenotypic readouts, replicated across multiple studies","pmids":["8790375"],"is_preprint":false},{"year":1997,"finding":"SP-A binds to Klebsiella pneumoniae K21a capsular polysaccharides containing Man-alpha1-Man sequences in a mannose-dependent manner (inhibited by mannan), opsonizes bacteria for alveolar macrophages via SP-A receptors, and activates macrophage mannose receptor-mediated phagocytosis; SP-A-mediated killing of K21a was demonstrated.","method":"SP-A agglutination assay, SP-A-coated particle binding to bacterial surface, binding to immobilized capsular polysaccharide, phagocytosis and killing assays with alveolar macrophages, mannan inhibition","journal":"The American journal of physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal binding and functional assays with inhibition controls; single lab rigorous study","pmids":["9124386"],"is_preprint":false},{"year":1997,"finding":"SP-A binds to Mycobacterium tuberculosis in a calcium- and concentration-dependent manner (Kd ~1.9 nM) via sugar moieties (deglycosylated SP-A has minimal binding); SP-A specifically binds a 60-kDa M. tuberculosis cell-wall protein; SP-A mediates M. tuberculosis attachment to murine alveolar macrophages, and this is blocked by anti-SP-A antibodies, mannosyl-BSA, and type V collagen.","method":"125I-SP-A binding assay, Kd determination, deglycosylation, ligand blot for 60-kDa cell-wall protein, 51Cr-labeled bacterial attachment assay, inhibition by antibodies and competing ligands","journal":"American journal of respiratory cell and molecular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — quantitative binding measurements with Kd, specific protein ligand identification, functional attachment assay with multiple inhibition controls","pmids":["9271309"],"is_preprint":false},{"year":1997,"finding":"SP-A binds BCG in a calcium-, carbohydrate-, and dose-dependent manner and enhances uptake of BCG-SP-A complexes by rat bone marrow macrophages, rat alveolar macrophages, and human monocytes; enhanced uptake is mediated in part by the 210-kDa SP-A receptor (SPR210) on macrophages, as anti-SPR210 antibodies block association.","method":"125I-SP-A binding to BCG, fluorescent microscopy cell-association assay, electron microscopy, SPR210 antibody blocking, receptor modulation experiments","journal":"The American journal of physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding assays, receptor antibody blocking, electron microscopy confirmation, multiple cell types; single rigorous study","pmids":["9176265"],"is_preprint":false},{"year":1994,"finding":"SP-A binds to influenza virus (A/X31) through its lectin domain in a calcium-dependent, saturable, concentration-dependent manner and inhibits virus-mediated hemagglutination; both SP-A and MBP bind a common 68-kDa viral neuraminidase; purified neuraminidase inhibits SP-A binding to intact virus.","method":"Saturation binding assay, hemagglutination inhibition assay, ligand blot analysis, neuraminidase isolation and competitive inhibition","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — identification of specific viral protein ligand by ligand blot, quantitative binding, and functional inhibition assay; single rigorous study","pmids":["7998980"],"is_preprint":false},{"year":1996,"finding":"Nitration of SP-A tyrosine residues in the carbohydrate recognition domain (CRD) by peroxynitrite (formed by NO + superoxide) decreases the ability of SP-A to aggregate lipids and bind mannose; the degree of functional inhibition correlates monotonically with nitrotyrosine content.","method":"SP-A exposure to peroxynitrite-generating systems (SIN-1, spermine NONOate + xanthine oxidase), nitrotyrosine quantification, mannose-binding assay, lipid aggregation assay, SOD and urate scavenger controls","journal":"Archives of biochemistry and biophysics","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro post-translational modification (nitration) with functional readouts and dose-response correlation; multiple scavenger controls confirming peroxynitrite mechanism","pmids":["8806782"],"is_preprint":false},{"year":1995,"finding":"SP-A receptor activity on macrophages is inversely regulated with respect to mannose receptor expression; agents that increase macrophage activation (PMA, LPS, IFN-γ) increase SP-A binding while decreasing mannose receptor activity; dexamethasone has the opposite effect.","method":"SP-A binding assay and mannose receptor activity assay on rat bone marrow macrophages and human monocytes treated with pharmacological agents and in vivo dexamethasone/LPS injection","journal":"The American journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional receptor binding assay with multiple pharmacological manipulations in vitro and in vivo; single lab","pmids":["8572233"],"is_preprint":false},{"year":1999,"finding":"Glycoprotein-340 (gp-340) co-purifies with SP-A from alveolar proteinosis lavage and binds SP-A in a calcium-dependent manner independent of SP-A lectin activity; however, gp-340 does not affect SP-A binding to alveolar macrophages or SP-A-stimulated macrophage chemotaxis, indicating gp-340 is not the SP-A receptor mediating chemotaxis.","method":"Co-purification and protein sequencing, SP-A binding inhibition assay, macrophage chemotaxis assay","journal":"American journal of respiratory cell and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein interaction with functional consequence tested; negative result for receptor role explicitly established; single lab","pmids":["10101009"],"is_preprint":false},{"year":1996,"finding":"SP-A-binding protein BP55 on type II pneumocyte cell membranes mediates SP-A-dependent lipid (DPPC liposome) uptake; this process is temperature-dependent, ATP-dependent, and blocked by an auto-anti-idiotypic antibody against BP55; SP-A-mediated uptake directs lipid to a non-degrading compartment.","method":"Liposome uptake assay in freshly isolated rat type II cells, ATP depletion, temperature dependence, anti-BP55 antibody inhibition","journal":"The American journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor antibody blocking identifies BP55 as functional mediator; multiple mechanistic controls; single lab","pmids":["8843792"],"is_preprint":false},{"year":2001,"finding":"After endocytosis in type II cells, SP-A and surfactant lipids first enter a common EEA1-positive early endosomal compartment; subsequently SP-A is rapidly recycled to the cell surface via Rab4-associated recycling vesicles and does not enter classic lamellar bodies, whereas lipid is directed to Rab7/CD63/lamellar body compartments; calmodulin inhibition blocks both components at the early endosome.","method":"Immunofluorescence with endosomal markers (EEA1, Rab4, Rab7, CD63, lamellar body marker 3C9), bafilomycin A1 and calmodulin inhibitor experiments in isolated rat type II cells","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple organelle markers, pharmacological perturbations, and identification of divergent SP-A vs lipid trafficking routes; single lab with orthogonal methods","pmids":["11435209"],"is_preprint":false},{"year":2004,"finding":"Neutrophil serine proteases (cathepsin G, elastase, proteinase-3) rapidly degrade SP-A at very low concentrations; cathepsin G is the most potent; these proteases are present in CF BAL fluid and cause time-dependent degradation of endogenous SP-A in CF BAL; degradation is blocked by serine protease inhibitors.","method":"In vitro protease degradation assay of purified SP-A and native BAL SP-A, dose-response and time-course with inhibitor (DFP, MNEI) controls","journal":"Thorax","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified components plus validation in native CF BAL fluid; multiple enzymes and inhibitor controls; single rigorous study","pmids":["15047952"],"is_preprint":false},{"year":2001,"finding":"Type II cells and alveolar macrophages contribute approximately equally to SP-A catabolism in vivo; macrophages are the primary catabolic cell (with ~80% of macrophage-associated label in lung-digest macrophages not recoverable by lavage).","method":"Intratracheal instillation of residualizing 125I-dilactitol-tyramine-SP-A in mice, time-course measurement of radioactivity in isolated type II cells, lavage macrophages, and lung-digest macrophages","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo residualizing label approach that distinguishes catabolism from uptake; single lab","pmids":["11350807"],"is_preprint":false},{"year":2001,"finding":"Amiodarone inhibits SP-A degradation by alveolar macrophages both in vitro and in vivo without affecting DPPC degradation; amiodarone perturbs lysosomal enzyme distribution and blocks the endocytic pathway after early endosomes; SP-A but not DPPC catabolism is thereby inhibited.","method":"Rabbit alveolar macrophage exposure to amiodarone in vitro, tracheal instillation with amiodarone in newborn rabbits, lysosomal enzyme distribution, endocytic tracer studies","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo corroborating data with mechanistic pathway analysis; single lab","pmids":["11597911"],"is_preprint":false},{"year":2003,"finding":"SP-A is required for increased DPPC uptake in response to hyperventilation or secretagogues in vivo; SP-A-/- mice fail to upregulate DPPC uptake under these stimuli; SP-A also modulates lysosomal-type phospholipase A2-mediated degradation of internalized DPPC.","method":"Intratracheal instillation of 3H-DPPC in SP-A +/+ and -/- mice, CO2-induced hyperventilation, secretagogue (8-Br-cAMP) treatment, PLA2 activity assay in isolated lungs","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — SP-A knockout with specific stimulus conditions, in vivo and ex vivo corroboration, enzymatic activity measurement; multiple orthogonal readouts","pmids":["12676766"],"is_preprint":false},{"year":1998,"finding":"SP-A(-/-) mice have markedly decreased tubular myelin, clear Group B Streptococci and Pseudomonas aeruginosa less efficiently than wild-type, and have normal phospholipid composition and surfactant clearance, demonstrating an in vivo role for SP-A in innate pulmonary defense.","method":"Gene-targeted SP-A knockout mice, bacterial clearance assay (intratracheal challenge), electron microscopy for tubular myelin, phospholipid analysis","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function with specific in vivo bacterial clearance readout, replicated across multiple studies","pmids":["9813377"],"is_preprint":false},{"year":2002,"finding":"In the absence of SP-A, influenza A virus clearance is decreased and lung inflammation is increased; exogenous SP-A restores viral clearance and reduces inflammation in SP-A-/- mice; SP-A deficiency is associated with decreased neutrophil myeloperoxidase activity and altered Th1/Th2 immune balance.","method":"Intranasal IAV infection of SP-A -/- vs +/+ mice, viral clearance measurement, BAL cytokine/lymphocyte analysis, myeloperoxidase activity assay, SP-A rescue experiment","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with pharmacological rescue, multiple mechanistic readouts (viral titer, cytokines, myeloperoxidase, lymphocyte subsets)","pmids":["11839553"],"is_preprint":false},{"year":1999,"finding":"SP-A enhances viral clearance of adenovirus from the lung and inhibits adenovirus-induced lung inflammation; SP-A-/- mice show increased PMN in BAL, elevated TNF-α, IL-6, IL-1β, and chemokine expression, and decreased alveolar macrophage uptake of adenovirus; co-administration of human SP-A to SP-A-/- mice ameliorates these defects.","method":"Intratracheal adenoviral infection of SP-A -/- vs +/+ mice, BAL analysis, cytokine mRNA and protein measurement, fluorescent adenovirus uptake by macrophages, SP-A rescue","journal":"The American journal of physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with rescue experiment, multiple cytokine and cellular readouts; single rigorous study","pmids":["10484466"],"is_preprint":false},{"year":2010,"finding":"Formation of tubular myelin (TM) in vivo requires both SP-A1 and SP-A2 gene products; humanized transgenic mice expressing only SP-A1 or only SP-A2 lack TM; TM is restored only when both gene products are present together; TM is absent in human BAL containing primarily one gene product and restored by exogenous SP-A containing both.","method":"Humanized transgenic mice (SP-A1 or SP-A2 cDNA-driven by SP-C promoter on SP-A KO background), electron microscopy for TM, Southern blot, immunohistochemistry, in vivo rescue with exogenous SP-A, human BAL analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo transgenic model with rescue, multiple orthogonal lines, corroborated in human BAL; multiple convergent experiments in one study","pmids":["20048345"],"is_preprint":false},{"year":2004,"finding":"Human SP-A2 variants enhance association of P. aeruginosa with rat alveolar macrophages more effectively than SP-A1 variants; SP-A2 phagocytic index is approximately 52–95% higher than SP-A1; co-expressed SP-A1/SP-A2 variants at certain concentrations are more active than single gene products.","method":"Light microscopy phagocytosis index assay with insect-cell-expressed human SP-A1 and SP-A2 variant proteins and rat alveolar macrophages","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional comparison of gene-specific recombinant proteins in phagocytosis assay; single lab","pmids":["15377498"],"is_preprint":false},{"year":2002,"finding":"SP-A1 and SP-A2 have different carbohydrate-binding specificities; SP-A2 binds with higher affinity to a wider variety of sugars than SP-A1 at both 1 and 5 mM Ca2+; all SP-A proteins bind fucose with highest affinity.","method":"Carbohydrate-binding assay with immobilized sugars using recombinant human SP-A1, SP-A2 proteins and native human alveolar SP-A at different calcium concentrations","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro binding assay with multiple sugars and calcium conditions; single lab, single method type","pmids":["12505869"],"is_preprint":false},{"year":2013,"finding":"SP-A suppresses TLR ligand-induced preterm delivery and inflammatory responses via a TLR2-dependent mechanism; SP-A inhibits LPS-, peptidoglycan-, and poly(I:C)-induced IL-1β, TNF-α, and CCL5 production, with the effect on PGN (TLR2 ligand) being TLR2-dependent as demonstrated in TLR2 knockout macrophages.","method":"Mouse macrophage cell line (RAW264.7), primary amniotic fluid and peritoneal macrophages from TLR4 and TLR2 knockout mice, cytokine ELISA, mouse preterm delivery model with intrauterine SP-A administration","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic receptor knockout (TLR2 KO) demonstrates pathway specificity; in vivo rescue experiment with multiple inflammatory readouts; single lab, multiple orthogonal methods","pmids":["23700442"],"is_preprint":false},{"year":2008,"finding":"SP-A permeabilizes rough LPS (Re-LPS) membranes by forming calcium-dependent protein-lipid aggregates on the membrane surface that extract LPS molecules from the membrane, decreasing van der Waals interactions between acyl chains and rendering the membrane leaky; coexistence of gel and fluid lipid phases in the LPS membrane is required for susceptibility to SP-A permeabilization.","method":"Epifluorescence microscopy of TR-SP-A on Re-LPS films, monolayer relaxation experiments, differential scanning calorimetry, membrane permeability assay","journal":"Biophysical journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — biophysical reconstitution with multiple complementary methods (microscopy, monolayer thermodynamics, DSC); single rigorous study establishing mechanism","pmids":["18599636"],"is_preprint":false},{"year":2009,"finding":"P63/CKAP4 functions as a receptor for SP-A on alveolar type II cells and mediates SP-A-dependent surfactant clearance; SP-A null mice deficient in clathrin-dependent uptake use an actin-mediated pathway; administration of SP-A to SP-A-null mice rescues the phenotype.","method":"SP-A receptor identification, SP-A gene-targeted mice, SP-A rescue experiment, pharmacological pathway analysis (clathrin vs. actin pathways) — review citing original experimental work","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor identified and rescue experiment described; this is a review citing original data; lower confidence due to indirect access via review abstract","pmids":["20054143"],"is_preprint":false},{"year":1990,"finding":"Phorbol ester (TPA) inhibits SP-A synthesis by decreasing de novo SP-A synthesis and SP-A mRNA levels in a time- and dose-dependent manner; the effect requires continued gene transcription and is not mediated solely by changes in SP-A transcription; actinomycin D blocks the rapid TPA-induced mRNA decrease, suggesting involvement of a labile destabilizing RNA species.","method":"35S-methionine incorporation in H441-4 adenocarcinoma cells, SP-A mRNA Northern blot, actinomycin D RNA stability assay, dose-response and kinetics of inhibition","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — metabolic labeling and mRNA stability assays with specific inhibitor controls; single lab","pmids":["2249989"],"is_preprint":false},{"year":1993,"finding":"Glucocorticoid inhibition of SP-A is receptor-mediated (blocked by RU 486), involves induction of a labile protein that decreases SP-A gene transcription (~60% reduction) and transiently reduces SP-A mRNA stability (t1/2 ~3 h initially vs ~8 h at steady state); the dominant response to glucocorticoid in fetal human lung is inhibition of SP-A mRNA.","method":"Human fetal lung explant culture with dexamethasone, nuclear elongation transcription assay, mRNA stability by actinomycin D and label-chase, cycloheximide, RU 486 blocking","journal":"The American journal of physiology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — nuclear run-on transcription assay plus mRNA stability measurement plus receptor-specificity (RU 486) and protein synthesis (cycloheximide) controls; multiple orthogonal methods","pmids":["8460712"],"is_preprint":false},{"year":1997,"finding":"Phorbol ester (TPA) acts primarily at the level of gene transcription to down-regulate SP-A in both H441 cells and human fetal lung explants, reducing SP-A gene transcription rate to ~28% of control.","method":"Nuclear elongation assay (run-on transcription), mRNA quantification, dose-response in H441 cells and human fetal lung explants","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — nuclear run-on transcription assay in two model systems; single lab","pmids":["9294011"],"is_preprint":false},{"year":1994,"finding":"SP-A1 and SP-A2 genes are differentially regulated: cAMP preferentially increases SP-A2 mRNA (~5-fold) over SP-A1 mRNA (~2-fold) in human fetal lung, while dexamethasone inhibits SP-A1 and SP-A2 equally (~70%); in H441 cells, dexamethasone inhibits SP-A1 but not SP-A2 mRNA, and cAMP increases both equally.","method":"Primer extension analysis of SP-A1 and SP-A2 mRNA in human fetal lung explants and H441 cells treated with DBcAMP, dexamethasone, and insulin","journal":"The American journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gene-specific primer extension with multiple hormonal treatments in two model systems; single lab","pmids":["8179013"],"is_preprint":false},{"year":2016,"finding":"A germline heterozygous missense mutation in SFTPA1 (p.Trp211Arg) located in the carbohydrate recognition domain impairs SP-A1 secretion, as demonstrated by functional studies; immunohistochemistry shows altered SP-A expression pattern in patient alveolar epithelium; this mutation segregates with IIP/IPF and lung adenocarcinoma.","method":"Germline mutation identification, in vitro functional secretion assay (cell transfection), immunohistochemistry on patient lung tissue","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro secretion assay with disease-associated mutation plus patient tissue validation; single lab","pmids":["26792177"],"is_preprint":false},{"year":2019,"finding":"A homozygous missense mutation in SFTPA1 disturbs SP-A1 protein secretion and causes IPF via necroptosis of alveolar epithelial type II cells; the cellular mechanism involves phosphorylation of IRE1α leading to JNK-mediated upregulation of RIPK3; JNK inhibition ameliorates pulmonary fibrosis in knock-in mice, and RIPK3 overexpression reverses this protection.","method":"Sftpa1 knock-in (KI) mice carrying patient mutation, secretion assay, IRE1α phosphorylation, JNK inhibitor treatment, RIPK3 overexpression, lung histology, influenza challenge","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — knock-in mouse model with pathway dissection (JNK inhibitor rescue + RIPK3 genetic overexpression reversal), multiple mechanistic readouts; single lab with rigorous genetic and pharmacological controls","pmids":["31601679"],"is_preprint":false},{"year":2020,"finding":"Pathogenic SFTPA1 (and SFTPA2) mutations preserve protein production but abolish secretion; this secretion defect is the shared functional consequence of 11 distinct mutations tested in vitro; SP-A expression pattern is altered in lung tissue of patients carrying these mutations.","method":"In vitro expression and secretion assay for 11 SFTPA1/SFTPA2 mutations in cell models, ex vivo immunostaining of patient lung tissue","journal":"The European respiratory journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — systematic functional assessment of 11 independent mutations with consistent result (secretion abolished, production preserved); in vitro + ex vivo corroboration; single lab but broad mutation panel","pmids":["32855221"],"is_preprint":false},{"year":2016,"finding":"Human SP-A1 allows pulmonary surfactant to achieve lower surface tension after adsorption and during compression-expansion cycling than surfactant with SP-A2 alone or no SP-A; SP-A1 also confers greater resistance to serum inhibition of surfactant function than equivalent amounts of SP-A2.","method":"Captive bubble surfactometer assay of humanized transgenic mouse surfactant (expressing SP-A1, SP-A2, or both), reconstituted porcine hydrophobic surfactant with recombinant SP-A1 or SP-A2 added","journal":"Biophysical journal","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — biophysical reconstitution assay with both transgenic and recombinant protein approach; single lab","pmids":["27508436"],"is_preprint":false},{"year":2011,"finding":"SP-A is produced by human endometrium/decidua and selectively inhibits prostaglandin F2α (PGF2α) production by term decidual stromal cells at a post-transcriptional level without affecting other inflammatory mediators; decidual SP-A expression decreases with labor onset.","method":"Immunohistochemistry and RT-PCR for SP-A localization, isolated decidual stromal cell culture with SP-A treatment, ELISA for PGF2α and other mediators, RT-PCR for eicosanoid gene expression","journal":"The Journal of clinical endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assay in primary human cells with post-transcriptional mechanism established (protein affected without gene expression change); single lab","pmids":["21270323"],"is_preprint":false},{"year":1996,"finding":"SP-A does not stimulate endocytosis of lipid vesicles by type II cells or MLE-12 cells but does cause surface aggregation of lipid; SP-B and SP-C stimulate lipid endocytosis, with SP-C being most potent; SP-A's role in surfactant recycling is thus distinct from SP-B and SP-C.","method":"Fluorescently labeled lipid vesicle binding and endocytosis assay at 4°C and 37°C in rat type II cells and MLE-12 cells with purified SP-A, SP-B, SP-C","journal":"The American journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct lipid uptake assay distinguishing SP-A from SP-B/C roles; single lab","pmids":["8772529"],"is_preprint":false},{"year":2009,"finding":"SP-A has a bacteriostatic effect on Mycoplasma pneumoniae by binding surface disaturated phosphatidylglycerols and the Mp membrane protein MPN372; SP-A deficiency leads to exaggerated inflammatory responses (TNF-α-driven) and more severe physiological consequences after Mp infection in mice.","method":"SP-A -/- vs. wild-type mouse infection with M. pneumoniae, airway hyperresponsiveness measurement, BAL cytokine analysis, pharmacological TNF-α inhibition","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with pharmacological pathway rescue (TNF-α inhibitor); direct binding to M. pneumoniae ligands described; single lab","pmids":["19494306"],"is_preprint":false}],"current_model":"SFTPA1-encoded SP-A1 is a calcium-dependent C-type lectin (collectin) that assembles into oligomers dependent on an intact collagenous domain; it specifically binds DPPC and other surfactant phospholipids through its carbohydrate recognition domain (CRD), is required for tubular myelin formation in vivo (a function that requires both SP-A1 and SP-A2 gene products), and is trafficked intracellularly via the endosomal system to lamellar bodies then recycled to the cell surface in a receptor-mediated (BP55/P63-CKAP4-dependent) manner; in innate immunity it acts as an opsonin by binding mannose-containing microbial ligands (bacterial capsular polysaccharides, mycobacterial cell-wall proteins, viral neuraminidase) and bridging pathogens to macrophage SP-A receptors (SPR210) to enhance phagocytosis, while also directly permeabilizing bacterial LPS membranes by forming protein-lipid aggregates; secretion of SP-A1 requires hydroxylation of its collagenous domain, and disease-causing missense mutations in the CRD abolish secretion and trigger necroptosis of alveolar type II cells via an IRE1α→JNK→RIPK3 pathway leading to pulmonary fibrosis; SP-A expression is regulated transcriptionally by cAMP (stimulatory), glucocorticoids (inhibitory, receptor-mediated, requiring new protein synthesis), and protein kinase C/phorbol esters (inhibitory at the transcriptional level), and its function is inactivated by peroxynitrite-mediated nitration of CRD tyrosines."},"narrative":{"mechanistic_narrative":"SFTPA1 encodes SP-A1, a calcium-dependent C-type lectin (collectin) that operates at the interface of pulmonary surfactant homeostasis and innate immune defense [PMID:1993679, PMID:9813377]. The protein assembles into large disulfide-bonded oligomers built on a collagen-like triple helix, and both oligomerization and downstream carbohydrate processing depend on an intact collagenous domain [PMID:2610270]; its C-terminal carbohydrate recognition domain (CRD) carries the higher-affinity calcium-binding site whose occupancy drives the conformational change and reversible aggregation underlying surfactant organization [PMID:2271565]. SP-A1 specifically binds DPPC and surfactant phospholipids through a mechanism requiring both the diacylglycerol moiety and the phosphocholine head group [PMID:1993679], enhances phospholipid adsorption and lowers surface tension at the air-liquid interface [PMID:2713385, PMID:27508436], and is genetically required — together with SP-A2 — for tubular myelin formation in vivo [PMID:8790375, PMID:20048345]. Secretion requires hydroxylation of the collagenous domain, without which high-mannose precursors accumulate intracellularly [PMID:3355864], and the protein traffics through an EEA1-positive early endosome before being recycled to the cell surface via Rab4 vesicles while surfactant lipid is diverted to Rab7/CD63 lamellar-body compartments [PMID:11435209], with P63/CKAP4 (and the SP-A-binding protein BP55) acting as the type II cell receptor for this clearance pathway [PMID:8843792, PMID:20054143]. In innate immunity SP-A1 functions as a calcium- and mannose-dependent opsonin, binding bacterial capsular polysaccharides, a 60-kDa mycobacterial cell-wall protein, and influenza neuraminidase, and bridging pathogens to macrophage receptors including the 210-kDa SPR210 to enhance phagocytosis and clearance [PMID:9124386, PMID:9271309, PMID:9176265, PMID:7998980]; it can also directly permeabilize LPS membranes by extracting LPS into calcium-dependent protein-lipid aggregates [PMID:18599636], and it restrains TLR-driven inflammation through a TLR2-dependent mechanism [PMID:23700442]. SP-A function is abolished by peroxynitrite-mediated nitration of CRD tyrosines and by neutrophil serine protease degradation [PMID:8806782, PMID:15047952]. Disease-causing missense mutations in the CRD abolish secretion while preserving protein production, and this secretory block triggers necroptosis of alveolar type II cells via an IRE1α→JNK→RIPK3 pathway, causing idiopathic pulmonary fibrosis [PMID:26792177, PMID:31601679, PMID:32855221].","teleology":[{"year":1989,"claim":"Established the structural basis of SP-A assembly, defining it as a collagenous oligomeric protein whose higher-order organization and calcium-dependent aggregation depend on an intact collagen-like domain.","evidence":"Collagenase digestion, circular dichroism, thermal denaturation, and disulfide mapping of purified SP-A","pmids":["2610270"],"confidence":"High","gaps":["No atomic-resolution structure of the oligomer","Stoichiometry of physiological oligomers not defined"]},{"year":1990,"claim":"Localized calcium binding to the CRD and linked calcium-induced conformational change to the reversible aggregation underlying surfactant organization, connecting a metal-binding event to function.","evidence":"Equilibrium dialysis, limited proteolysis fragments, and intrinsic fluorescence of SP-A","pmids":["2271565"],"confidence":"High","gaps":["Structural detail of the calcium-induced conformational change unresolved"]},{"year":1991,"claim":"Defined the lipid-binding specificity of SP-A, showing it recognizes DPPC via both acyl and head-group features and that the collagenous (not glycan) domain is required, mechanistically distinguishing lipid binding from lectin activity.","evidence":"125I-SP-A thin-layer chromatogram overlay binding assays with domain-deletion and chemical variants","pmids":["1993679"],"confidence":"High","gaps":["Did not resolve how lipid and carbohydrate binding are coordinated in vivo"]},{"year":1988,"claim":"Showed that collagenous-domain hydroxylation gates intracellular transport and secretion, establishing a post-translational checkpoint for SP-A maturation.","evidence":"Metabolic labeling and subcellular fractionation of primary type II cells with prolyl-hydroxylation inhibitors","pmids":["3355864"],"confidence":"High","gaps":["Did not identify the trafficking receptor or quality-control machinery"]},{"year":1993,"claim":"Demonstrated receptor-mediated endocytic recycling of SP-A into lamellar bodies by type II cells, framing SP-A as a recycled component of surfactant homeostasis.","evidence":"Electron microscopy of SP-A-colloidal gold conjugates with competitive inhibition in rat type II cells","pmids":["8417113"],"confidence":"Medium","gaps":["Receptor identity not established at this stage","Single-lab EM-based readout"]},{"year":1996,"claim":"Identified BP55 as a functional type II-cell receptor mediating SP-A-dependent, ATP-dependent lipid uptake to a non-degrading compartment, providing the first molecular handle on the recycling receptor.","evidence":"Liposome uptake assay in rat type II cells with anti-BP55 antibody inhibition and ATP/temperature dependence","pmids":["8843792"],"confidence":"Medium","gaps":["Molecular identity of BP55 not cloned here","Single antibody-based inhibition"]},{"year":2001,"claim":"Resolved that SP-A and surfactant lipid share an early endosome but then diverge — SP-A recycles via Rab4 vesicles while lipid routes to lamellar bodies — clarifying that SP-A is recycled rather than co-trafficked with its cargo.","evidence":"Immunofluorescence with endosomal markers plus bafilomycin and calmodulin inhibitors in rat type II cells","pmids":["11435209"],"confidence":"High","gaps":["Did not name the receptor driving the divergence"]},{"year":2009,"claim":"Named P63/CKAP4 as the SP-A receptor on type II cells mediating surfactant clearance, connecting recycling to a defined protein and rescuable phenotype.","evidence":"Receptor identification and SP-A rescue in SP-A-null mice (review citing original work)","pmids":["20054143"],"confidence":"Medium","gaps":["Accessed via review","Relationship between P63/CKAP4 and BP55 not reconciled in timeline"]},{"year":1996,"claim":"A null mouse demonstrated that SP-A is specifically required for tubular myelin assembly while being dispensable for bulk surfactant pool size and lung mechanics, isolating its in vivo structural role.","evidence":"Homologous-recombination SP-A knockout with EM, lipid analysis, and lung function measurements","pmids":["8790375"],"confidence":"High","gaps":["Molecular mechanism of tubular myelin assembly not defined"]},{"year":2010,"claim":"Showed that tubular myelin formation requires both SP-A1 and SP-A2 gene products together, establishing functional non-redundancy between the two paralogs in vivo.","evidence":"Humanized SP-A1-only and SP-A2-only transgenic mice with EM and exogenous SP-A rescue, corroborated in human BAL","pmids":["20048345"],"confidence":"High","gaps":["Stoichiometric/structural basis for the SP-A1/SP-A2 requirement not resolved"]},{"year":1994,"claim":"Established SP-A as a mannose-dependent calcium-dependent opsonin recognizing diverse microbial ligands, defining its lectin-based innate-immune mechanism.","evidence":"Influenza saturation binding, hemagglutination inhibition, and ligand-blot identification of viral neuraminidase","pmids":["7998980"],"confidence":"High","gaps":["Did not test in vivo consequence at this stage"]},{"year":1997,"claim":"Extended opsonic recognition to bacterial and mycobacterial ligands and identified the 210-kDa macrophage SP-A receptor (SPR210) bridging pathogens to phagocytes.","evidence":"Binding and phagocytosis/killing assays for Klebsiella polysaccharide, M. tuberculosis 60-kDa protein, and BCG with anti-SPR210 blocking","pmids":["9124386","9271309","9176265"],"confidence":"High","gaps":["SPR210 molecular identity and signaling not fully defined"]},{"year":1998,"claim":"Genetic knockout confirmed in vivo that SP-A is required for efficient bacterial clearance, validating its opsonic role at the organismal level.","evidence":"Intratracheal bacterial challenge of SP-A-/- mice with clearance and tubular myelin readouts","pmids":["9813377"],"confidence":"High","gaps":["Did not dissect macrophage signaling downstream of opsonization"]},{"year":2002,"claim":"Demonstrated, with knockout and rescue, that SP-A both promotes viral clearance and restrains lung inflammation, showing a dual antimicrobial and immunomodulatory function in vivo.","evidence":"IAV and adenovirus infection of SP-A-/- mice with SP-A rescue and cytokine/clearance readouts","pmids":["11839553","10484466"],"confidence":"High","gaps":["Did not identify the receptor mediating the anti-inflammatory effect"]},{"year":2013,"claim":"Defined a TLR2-dependent anti-inflammatory mechanism, showing SP-A suppresses TLR-ligand-induced cytokines and preterm delivery through a specific receptor pathway.","evidence":"Cytokine assays in TLR2/TLR4 knockout macrophages and an in vivo preterm-delivery model","pmids":["23700442"],"confidence":"High","gaps":["Direct SP-A/TLR2 physical interaction not shown","Mechanism for non-TLR2 ligands unresolved"]},{"year":2008,"claim":"Revealed a direct, non-opsonic bactericidal mechanism whereby SP-A permeabilizes LPS membranes by extracting lipid into calcium-dependent protein-lipid aggregates.","evidence":"Epifluorescence microscopy, monolayer relaxation, and DSC on Re-LPS films with SP-A","pmids":["18599636"],"confidence":"High","gaps":["In vivo relevance of direct permeabilization vs opsonization not quantified"]},{"year":1996,"claim":"Showed SP-A function is inactivated by peroxynitrite nitration of CRD tyrosines, linking oxidative/nitrosative stress to loss of surfactant and immune activity.","evidence":"Peroxynitrite exposure with nitrotyrosine quantification and lipid-aggregation/mannose-binding assays with scavenger controls","pmids":["8806782"],"confidence":"High","gaps":["In vivo extent of nitration during disease not established here"]},{"year":2004,"claim":"Identified neutrophil serine proteases as efficient inactivators of SP-A in inflamed (cystic fibrosis) airways, providing a disease-relevant degradation mechanism.","evidence":"In vitro protease degradation of purified and native BAL SP-A with inhibitor controls","pmids":["15047952"],"confidence":"High","gaps":["Functional consequence of degradation in patients not directly measured"]},{"year":1994,"claim":"Established hormonal and gene-specific transcriptional control of SP-A, with cAMP stimulatory and glucocorticoids/phorbol esters inhibitory, defining regulatory inputs.","evidence":"Primer extension, nuclear run-on transcription, and mRNA stability assays in fetal lung explants and H441 cells with RU486/cycloheximide controls","pmids":["8179013","8460712","2249989","9294011"],"confidence":"High","gaps":["Specific transcription factors and labile mediators not identified"]},{"year":2016,"claim":"Linked SFTPA1 CRD missense mutations to impaired secretion and familial pulmonary fibrosis, establishing SFTPA1 as a Mendelian disease gene.","evidence":"Germline mutation identification, in vitro secretion assay, and patient lung immunohistochemistry","pmids":["26792177"],"confidence":"Medium","gaps":["Cellular death mechanism not yet defined at this stage","Single-family/single-lab functional assay"]},{"year":2019,"claim":"Defined the cellular pathomechanism of mutant SP-A1, showing that secretion failure triggers type II-cell necroptosis through IRE1α→JNK→RIPK3, with genetic and pharmacological rescue establishing causality.","evidence":"Sftpa1 knock-in mice with IRE1α/JNK/RIPK3 dissection, JNK inhibitor rescue, and RIPK3 overexpression reversal","pmids":["31601679"],"confidence":"High","gaps":["Mechanism connecting retained protein to IRE1α activation not fully resolved"]},{"year":2020,"claim":"Generalized the disease mechanism by showing that 11 distinct SFTPA1/SFTPA2 mutations share a common abolition of secretion with preserved production, defining a unified molecular signature of pathogenicity.","evidence":"Systematic in vitro expression/secretion assays for 11 mutations with ex vivo patient tissue immunostaining","pmids":["32855221"],"confidence":"High","gaps":["Whether all mutations converge on the same necroptotic pathway not tested"]},{"year":null,"claim":"How SP-A1 oligomers physically template tubular myelin in cooperation with SP-A2, and how the retained mutant protein activates the IRE1α ER-stress sensor, remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structure of the tubular-myelin lattice","Molecular link between secretion block and IRE1α activation undefined","Reconciliation of BP55, P63/CKAP4, and SPR210 receptor identities incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,5,31]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[11,12,13,14]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[30,41]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[3,5,24]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[9,19]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[3,4]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[11,24,25,30]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[9,19,18]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[38]}],"complexes":[],"partners":["SFTPA2","CKAP4","TLR2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IWL2","full_name":"Pulmonary surfactant-associated protein A1","aliases":["35 kDa pulmonary surfactant-associated protein","Alveolar proteinosis protein","Collectin-4"],"length_aa":248,"mass_kda":26.2,"function":"In presence of calcium ions, it binds to surfactant phospholipids and contributes to lower the surface tension at the air-liquid interface in the alveoli of the mammalian lung and is essential for normal respiration. Enhances the expression of MYO18A/SP-R210 on alveolar macrophages (By similarity) (Microbial infection) Recognition of M.tuberculosis by dendritic cells may occur partially via this molecule (PubMed:17158455, PubMed:21203928). Can recognize, bind, and opsonize pathogens to enhance their elimination by alveolar macrophages (PubMed:21123169) (Microbial infection) Binds M.pneumoniae CARDS toxin, serves as one receptor for this pathogen (PubMed:15845487, PubMed:25139904). When SFTPA1 is down-regulated by siRNA, less toxin binds to human cells and less vacuolization (a symptom of M.pneumoniae infection) is seen (PubMed:25139904)","subcellular_location":"Secreted; Secreted, extracellular space, extracellular matrix; Secreted, extracellular space, surface film","url":"https://www.uniprot.org/uniprotkb/Q8IWL2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SFTPA1","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1165,"dependency_fraction":0.004291845493562232},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SFTPA1","total_profiled":1310},"omim":[{"mim_id":"619611","title":"INTERSTITIAL LUNG DISEASE 1; ILD1","url":"https://www.omim.org/entry/619611"},{"mim_id":"610913","title":"SURFACTANT METABOLISM DYSFUNCTION, PULMONARY, 2; SMDP2","url":"https://www.omim.org/entry/610913"},{"mim_id":"607948","title":"MYCOBACTERIUM TUBERCULOSIS, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/607948"},{"mim_id":"606531","title":"SECRETOGLOBIN, FAMILY 3A, MEMBER 2; SCGB3A2","url":"https://www.omim.org/entry/606531"},{"mim_id":"602039","title":"EUKARYOTIC TRANSLATION INITIATION FACTOR 3, SUBUNIT A; EIF3A","url":"https://www.omim.org/entry/602039"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"lung","ntpm":6679.7}],"url":"https://www.proteinatlas.org/search/SFTPA1"},"hgnc":{"alias_symbol":["SP-A","SP-A1","COLEC4"],"prev_symbol":["SFTP1"]},"alphafold":{"accession":"Q8IWL2","domains":[{"cath_id":"3.10.100.10","chopping":"133-246","consensus_level":"high","plddt":96.8712,"start":133,"end":246}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IWL2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IWL2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IWL2-F1-predicted_aligned_error_v6.png","plddt_mean":81.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SFTPA1","jax_strain_url":"https://www.jax.org/strain/search?query=SFTPA1"},"sequence":{"accession":"Q8IWL2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IWL2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IWL2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IWL2"}},"corpus_meta":[{"pmid":"16213021","id":"PMC_16213021","title":"Surfactant proteins SP-A and SP-D: structure, function and receptors.","date":"2005","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/16213021","citation_count":413,"is_preprint":false},{"pmid":"8790375","id":"PMC_8790375","title":"Altered surfactant function and structure in SP-A gene targeted mice.","date":"1996","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/8790375","citation_count":350,"is_preprint":false},{"pmid":"15589315","id":"PMC_15589315","title":"The lung collectins, SP-A and SP-D, modulate pulmonary innate immunity.","date":"2005","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/15589315","citation_count":157,"is_preprint":false},{"pmid":"11076040","id":"PMC_11076040","title":"Polymorphisms of human SP-A, SP-B, and SP-D genes: association of SP-B Thr131Ile with ARDS.","date":"2000","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11076040","citation_count":154,"is_preprint":false},{"pmid":"1993679","id":"PMC_1993679","title":"Pulmonary surfactant protein A (SP-A) specifically binds dipalmitoylphosphatidylcholine.","date":"1991","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/1993679","citation_count":149,"is_preprint":false},{"pmid":"1372511","id":"PMC_1372511","title":"Characterization of a second human pulmonary surfactant-associated protein SP-A gene.","date":"1992","source":"American journal of respiratory cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/1372511","citation_count":122,"is_preprint":false},{"pmid":"33542724","id":"PMC_33542724","title":"SP-A and SP-D: Dual Functioning Immune Molecules With Antiviral and Immunomodulatory Properties.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33542724","citation_count":121,"is_preprint":false},{"pmid":"23715088","id":"PMC_23715088","title":"Blood biomarkers MMP-7 and SP-A: predictors of outcome in idiopathic pulmonary fibrosis.","date":"2013","source":"Chest","url":"https://pubmed.ncbi.nlm.nih.gov/23715088","citation_count":114,"is_preprint":false},{"pmid":"11839553","id":"PMC_11839553","title":"Absence of SP-A modulates innate and adaptive defense responses to pulmonary influenza infection.","date":"2002","source":"American journal of physiology. 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binding requires the intact collagenous domain but not the oligosaccharide moiety; the nonpolar diacylglycerol group and the specific polar head group (phosphocholine) are both required; deglycosylated SP-A retains binding but the collagenase-resistant collagenous fragment does not.\",\n      \"method\": \"125I-SP-A thin-layer chromatogram overlay binding assay, EGTA inhibition, phospholipase C/A2 treatments, competitive inhibition with deglycosylated and collagenase-resistant SP-A fragments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro binding assay with multiple domain-deletion and chemical variants, replicated across multiple lipid species and conditions in a single rigorous study\",\n      \"pmids\": [\"1993679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"SP-A forms large oligomers dependent on an intact collagen-like domain; the cysteines in the non-collagen domain form intrachain disulfide bonds (between residues 135–226 and 204–218); the protein has a collagen-like triple helix and exhibits calcium-dependent aggregation at physiological calcium concentrations.\",\n      \"method\": \"Collagenase digestion, circular dichroism spectroscopy, thermal denaturation, disulfide bond mapping\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural characterization by multiple orthogonal biochemical methods (CD, collagenase digestion, thermal stability) in a single rigorous study\",\n      \"pmids\": [\"2610270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"Each SP-A monomer binds two to three calcium ions; the higher-affinity calcium-binding site is located in the C-terminal carbohydrate recognition domain (CRD); calcium binding to this domain causes a conformational change and promotes reversible protein aggregation relevant to tubular myelin formation.\",\n      \"method\": \"Equilibrium dialysis, gel permeation chromatography, limited proteolysis fragment studies, intrinsic fluorescence spectroscopy\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro binding measurements with domain-specific fragment validation and multiple orthogonal methods in one study\",\n      \"pmids\": [\"2271565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"The hydroxylation of the collagenous domain of SP-A is required for its intracellular transport to the lamellar body fraction and secretion; disruption of triple-helix formation (by alpha,alpha'-dipyridyl or cis-4-hydroxy-L-proline) causes accumulation of high-mannose precursors intracellularly without secretion; carbohydrate processing (sialylation) is also dependent on an intact collagenous domain.\",\n      \"method\": \"Metabolic labeling of type II cells, inhibitor treatment, subcellular fractionation, endoglycosidase H resistance assay\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in primary type II cells with specific chemical inhibitors and biochemical fractionation, multiple orthogonal endpoints\",\n      \"pmids\": [\"3355864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"After intratracheal instillation, both SP-A protein and surfactant lipids are taken up by lung cells and incorporated into lamellar body-enriched secretory granules in a time-dependent manner, consistent with receptor-mediated recycling.\",\n      \"method\": \"Intratracheal instillation of radiolabeled lipid-SP-A complex, subcellular fractionation on discontinuous sucrose density gradients\",\n      \"journal\": \"Journal of applied physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo subcellular fractionation with dual radiolabels, single lab\",\n      \"pmids\": [\"2708254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"SP-A enhances the surface activity of lipid extract surfactant by improving the rate of phospholipid adsorption and spreading at the air-liquid interface, resulting in stable lipid monolayer formation at lower phospholipid and calcium concentrations.\",\n      \"method\": \"Pulsating bubble surfactometer assay of lipid extract surfactant reconstituted with purified SP-A\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro functional reconstitution assay, single lab, single method\",\n      \"pmids\": [\"2713385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"SP-A interacts with alveolar macrophages via a specific, mannose-dependent receptor distinct from the classical mannose receptor; binding and uptake occur via coated pits/vesicles and material is transported to secondary lysosomes; excess SP-A competitively inhibits uptake.\",\n      \"method\": \"Electron microscopy of SP-A-coated gold particles incubated with rat alveolar macrophages, competitive inhibition with mannan-BSA/galactosyl-BSA, mannose receptor down-regulation experiments\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — electron microscopy with gold-labeled ligand, competitive inhibition, receptor specificity controls; single lab\",\n      \"pmids\": [\"1846339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"SP-A uptake by macrophages and monocytes is mannose-dependent; the interaction is mediated at least in part by SP-A binding to mannose residues on the macrophage surface (not solely via the mannose receptor), as monocytes lacking mannose receptor activity still internalize SP-A gold particles in a mannose-dependent manner.\",\n      \"method\": \"Electron microscopy of SP-A-coated gold particles with human macrophages/monocytes, competitive inhibition with mannosyl-BSA vs galactosyl-BSA, ConA labeling of cell surface\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — electron microscopy with receptor-specificity controls, monocyte vs macrophage comparison; single lab\",\n      \"pmids\": [\"2627938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"SP-A enhances serum-independent phagocytosis of several bacterial species (E. coli, P. aeruginosa, S. aureus) by alveolar macrophages in a concentration-dependent manner; the effect is species- and growth-phase-dependent; more complex oligomeric SP-A is most effective.\",\n      \"method\": \"Phagocytosis assay of non-opsonized bacteria with purified SP-A variants (recombinant human SP-A1, SP-A2, and proteinosis-derived SP-A) and isolated alveolar macrophages\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct phagocytosis assay with multiple SP-A forms and bacterial species; single lab\",\n      \"pmids\": [\"1639094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"SP-A is internalized by alveolar type II cells via the endosomal system (including multivesicular bodies) into lamellar bodies; internalization is receptor-mediated (inhibited by excess unlabeled SP-A and by alkylation); cell shape/cytoskeletal organization regulates SP-A recycling efficiency.\",\n      \"method\": \"Electron microscopy of SP-A-colloidal gold conjugates in primary rat type II cells, competitive inhibition, fluid-phase marker co-internalization\",\n      \"journal\": \"The journal of histochemistry and cytochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct electron microscopy with gold conjugates and receptor-specificity controls; single lab\",\n      \"pmids\": [\"8417113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"A null mutation of the murine SP-A gene eliminates tubular myelin formation in the lung without altering postnatal survival, lung morphology, surfactant phospholipid pool sizes, SP-B/C/D levels, or lung compliance; SP-A is specifically required for tubular myelin assembly.\",\n      \"method\": \"Homologous recombination gene targeting in mice (SP-A -/- knockout), electron microscopy, lung function measurements, lipid analysis, Northern/Western blot\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic knockout with multiple orthogonal phenotypic readouts, replicated across multiple studies\",\n      \"pmids\": [\"8790375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"SP-A binds to Klebsiella pneumoniae K21a capsular polysaccharides containing Man-alpha1-Man sequences in a mannose-dependent manner (inhibited by mannan), opsonizes bacteria for alveolar macrophages via SP-A receptors, and activates macrophage mannose receptor-mediated phagocytosis; SP-A-mediated killing of K21a was demonstrated.\",\n      \"method\": \"SP-A agglutination assay, SP-A-coated particle binding to bacterial surface, binding to immobilized capsular polysaccharide, phagocytosis and killing assays with alveolar macrophages, mannan inhibition\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal binding and functional assays with inhibition controls; single lab rigorous study\",\n      \"pmids\": [\"9124386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"SP-A binds to Mycobacterium tuberculosis in a calcium- and concentration-dependent manner (Kd ~1.9 nM) via sugar moieties (deglycosylated SP-A has minimal binding); SP-A specifically binds a 60-kDa M. tuberculosis cell-wall protein; SP-A mediates M. tuberculosis attachment to murine alveolar macrophages, and this is blocked by anti-SP-A antibodies, mannosyl-BSA, and type V collagen.\",\n      \"method\": \"125I-SP-A binding assay, Kd determination, deglycosylation, ligand blot for 60-kDa cell-wall protein, 51Cr-labeled bacterial attachment assay, inhibition by antibodies and competing ligands\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — quantitative binding measurements with Kd, specific protein ligand identification, functional attachment assay with multiple inhibition controls\",\n      \"pmids\": [\"9271309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"SP-A binds BCG in a calcium-, carbohydrate-, and dose-dependent manner and enhances uptake of BCG-SP-A complexes by rat bone marrow macrophages, rat alveolar macrophages, and human monocytes; enhanced uptake is mediated in part by the 210-kDa SP-A receptor (SPR210) on macrophages, as anti-SPR210 antibodies block association.\",\n      \"method\": \"125I-SP-A binding to BCG, fluorescent microscopy cell-association assay, electron microscopy, SPR210 antibody blocking, receptor modulation experiments\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding assays, receptor antibody blocking, electron microscopy confirmation, multiple cell types; single rigorous study\",\n      \"pmids\": [\"9176265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"SP-A binds to influenza virus (A/X31) through its lectin domain in a calcium-dependent, saturable, concentration-dependent manner and inhibits virus-mediated hemagglutination; both SP-A and MBP bind a common 68-kDa viral neuraminidase; purified neuraminidase inhibits SP-A binding to intact virus.\",\n      \"method\": \"Saturation binding assay, hemagglutination inhibition assay, ligand blot analysis, neuraminidase isolation and competitive inhibition\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — identification of specific viral protein ligand by ligand blot, quantitative binding, and functional inhibition assay; single rigorous study\",\n      \"pmids\": [\"7998980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Nitration of SP-A tyrosine residues in the carbohydrate recognition domain (CRD) by peroxynitrite (formed by NO + superoxide) decreases the ability of SP-A to aggregate lipids and bind mannose; the degree of functional inhibition correlates monotonically with nitrotyrosine content.\",\n      \"method\": \"SP-A exposure to peroxynitrite-generating systems (SIN-1, spermine NONOate + xanthine oxidase), nitrotyrosine quantification, mannose-binding assay, lipid aggregation assay, SOD and urate scavenger controls\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro post-translational modification (nitration) with functional readouts and dose-response correlation; multiple scavenger controls confirming peroxynitrite mechanism\",\n      \"pmids\": [\"8806782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"SP-A receptor activity on macrophages is inversely regulated with respect to mannose receptor expression; agents that increase macrophage activation (PMA, LPS, IFN-γ) increase SP-A binding while decreasing mannose receptor activity; dexamethasone has the opposite effect.\",\n      \"method\": \"SP-A binding assay and mannose receptor activity assay on rat bone marrow macrophages and human monocytes treated with pharmacological agents and in vivo dexamethasone/LPS injection\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional receptor binding assay with multiple pharmacological manipulations in vitro and in vivo; single lab\",\n      \"pmids\": [\"8572233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Glycoprotein-340 (gp-340) co-purifies with SP-A from alveolar proteinosis lavage and binds SP-A in a calcium-dependent manner independent of SP-A lectin activity; however, gp-340 does not affect SP-A binding to alveolar macrophages or SP-A-stimulated macrophage chemotaxis, indicating gp-340 is not the SP-A receptor mediating chemotaxis.\",\n      \"method\": \"Co-purification and protein sequencing, SP-A binding inhibition assay, macrophage chemotaxis assay\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein interaction with functional consequence tested; negative result for receptor role explicitly established; single lab\",\n      \"pmids\": [\"10101009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"SP-A-binding protein BP55 on type II pneumocyte cell membranes mediates SP-A-dependent lipid (DPPC liposome) uptake; this process is temperature-dependent, ATP-dependent, and blocked by an auto-anti-idiotypic antibody against BP55; SP-A-mediated uptake directs lipid to a non-degrading compartment.\",\n      \"method\": \"Liposome uptake assay in freshly isolated rat type II cells, ATP depletion, temperature dependence, anti-BP55 antibody inhibition\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor antibody blocking identifies BP55 as functional mediator; multiple mechanistic controls; single lab\",\n      \"pmids\": [\"8843792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"After endocytosis in type II cells, SP-A and surfactant lipids first enter a common EEA1-positive early endosomal compartment; subsequently SP-A is rapidly recycled to the cell surface via Rab4-associated recycling vesicles and does not enter classic lamellar bodies, whereas lipid is directed to Rab7/CD63/lamellar body compartments; calmodulin inhibition blocks both components at the early endosome.\",\n      \"method\": \"Immunofluorescence with endosomal markers (EEA1, Rab4, Rab7, CD63, lamellar body marker 3C9), bafilomycin A1 and calmodulin inhibitor experiments in isolated rat type II cells\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple organelle markers, pharmacological perturbations, and identification of divergent SP-A vs lipid trafficking routes; single lab with orthogonal methods\",\n      \"pmids\": [\"11435209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Neutrophil serine proteases (cathepsin G, elastase, proteinase-3) rapidly degrade SP-A at very low concentrations; cathepsin G is the most potent; these proteases are present in CF BAL fluid and cause time-dependent degradation of endogenous SP-A in CF BAL; degradation is blocked by serine protease inhibitors.\",\n      \"method\": \"In vitro protease degradation assay of purified SP-A and native BAL SP-A, dose-response and time-course with inhibitor (DFP, MNEI) controls\",\n      \"journal\": \"Thorax\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified components plus validation in native CF BAL fluid; multiple enzymes and inhibitor controls; single rigorous study\",\n      \"pmids\": [\"15047952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Type II cells and alveolar macrophages contribute approximately equally to SP-A catabolism in vivo; macrophages are the primary catabolic cell (with ~80% of macrophage-associated label in lung-digest macrophages not recoverable by lavage).\",\n      \"method\": \"Intratracheal instillation of residualizing 125I-dilactitol-tyramine-SP-A in mice, time-course measurement of radioactivity in isolated type II cells, lavage macrophages, and lung-digest macrophages\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo residualizing label approach that distinguishes catabolism from uptake; single lab\",\n      \"pmids\": [\"11350807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Amiodarone inhibits SP-A degradation by alveolar macrophages both in vitro and in vivo without affecting DPPC degradation; amiodarone perturbs lysosomal enzyme distribution and blocks the endocytic pathway after early endosomes; SP-A but not DPPC catabolism is thereby inhibited.\",\n      \"method\": \"Rabbit alveolar macrophage exposure to amiodarone in vitro, tracheal instillation with amiodarone in newborn rabbits, lysosomal enzyme distribution, endocytic tracer studies\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo corroborating data with mechanistic pathway analysis; single lab\",\n      \"pmids\": [\"11597911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SP-A is required for increased DPPC uptake in response to hyperventilation or secretagogues in vivo; SP-A-/- mice fail to upregulate DPPC uptake under these stimuli; SP-A also modulates lysosomal-type phospholipase A2-mediated degradation of internalized DPPC.\",\n      \"method\": \"Intratracheal instillation of 3H-DPPC in SP-A +/+ and -/- mice, CO2-induced hyperventilation, secretagogue (8-Br-cAMP) treatment, PLA2 activity assay in isolated lungs\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — SP-A knockout with specific stimulus conditions, in vivo and ex vivo corroboration, enzymatic activity measurement; multiple orthogonal readouts\",\n      \"pmids\": [\"12676766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"SP-A(-/-) mice have markedly decreased tubular myelin, clear Group B Streptococci and Pseudomonas aeruginosa less efficiently than wild-type, and have normal phospholipid composition and surfactant clearance, demonstrating an in vivo role for SP-A in innate pulmonary defense.\",\n      \"method\": \"Gene-targeted SP-A knockout mice, bacterial clearance assay (intratracheal challenge), electron microscopy for tubular myelin, phospholipid analysis\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function with specific in vivo bacterial clearance readout, replicated across multiple studies\",\n      \"pmids\": [\"9813377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"In the absence of SP-A, influenza A virus clearance is decreased and lung inflammation is increased; exogenous SP-A restores viral clearance and reduces inflammation in SP-A-/- mice; SP-A deficiency is associated with decreased neutrophil myeloperoxidase activity and altered Th1/Th2 immune balance.\",\n      \"method\": \"Intranasal IAV infection of SP-A -/- vs +/+ mice, viral clearance measurement, BAL cytokine/lymphocyte analysis, myeloperoxidase activity assay, SP-A rescue experiment\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with pharmacological rescue, multiple mechanistic readouts (viral titer, cytokines, myeloperoxidase, lymphocyte subsets)\",\n      \"pmids\": [\"11839553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"SP-A enhances viral clearance of adenovirus from the lung and inhibits adenovirus-induced lung inflammation; SP-A-/- mice show increased PMN in BAL, elevated TNF-α, IL-6, IL-1β, and chemokine expression, and decreased alveolar macrophage uptake of adenovirus; co-administration of human SP-A to SP-A-/- mice ameliorates these defects.\",\n      \"method\": \"Intratracheal adenoviral infection of SP-A -/- vs +/+ mice, BAL analysis, cytokine mRNA and protein measurement, fluorescent adenovirus uptake by macrophages, SP-A rescue\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with rescue experiment, multiple cytokine and cellular readouts; single rigorous study\",\n      \"pmids\": [\"10484466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Formation of tubular myelin (TM) in vivo requires both SP-A1 and SP-A2 gene products; humanized transgenic mice expressing only SP-A1 or only SP-A2 lack TM; TM is restored only when both gene products are present together; TM is absent in human BAL containing primarily one gene product and restored by exogenous SP-A containing both.\",\n      \"method\": \"Humanized transgenic mice (SP-A1 or SP-A2 cDNA-driven by SP-C promoter on SP-A KO background), electron microscopy for TM, Southern blot, immunohistochemistry, in vivo rescue with exogenous SP-A, human BAL analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo transgenic model with rescue, multiple orthogonal lines, corroborated in human BAL; multiple convergent experiments in one study\",\n      \"pmids\": [\"20048345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Human SP-A2 variants enhance association of P. aeruginosa with rat alveolar macrophages more effectively than SP-A1 variants; SP-A2 phagocytic index is approximately 52–95% higher than SP-A1; co-expressed SP-A1/SP-A2 variants at certain concentrations are more active than single gene products.\",\n      \"method\": \"Light microscopy phagocytosis index assay with insect-cell-expressed human SP-A1 and SP-A2 variant proteins and rat alveolar macrophages\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional comparison of gene-specific recombinant proteins in phagocytosis assay; single lab\",\n      \"pmids\": [\"15377498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SP-A1 and SP-A2 have different carbohydrate-binding specificities; SP-A2 binds with higher affinity to a wider variety of sugars than SP-A1 at both 1 and 5 mM Ca2+; all SP-A proteins bind fucose with highest affinity.\",\n      \"method\": \"Carbohydrate-binding assay with immobilized sugars using recombinant human SP-A1, SP-A2 proteins and native human alveolar SP-A at different calcium concentrations\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro binding assay with multiple sugars and calcium conditions; single lab, single method type\",\n      \"pmids\": [\"12505869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SP-A suppresses TLR ligand-induced preterm delivery and inflammatory responses via a TLR2-dependent mechanism; SP-A inhibits LPS-, peptidoglycan-, and poly(I:C)-induced IL-1β, TNF-α, and CCL5 production, with the effect on PGN (TLR2 ligand) being TLR2-dependent as demonstrated in TLR2 knockout macrophages.\",\n      \"method\": \"Mouse macrophage cell line (RAW264.7), primary amniotic fluid and peritoneal macrophages from TLR4 and TLR2 knockout mice, cytokine ELISA, mouse preterm delivery model with intrauterine SP-A administration\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic receptor knockout (TLR2 KO) demonstrates pathway specificity; in vivo rescue experiment with multiple inflammatory readouts; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"23700442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SP-A permeabilizes rough LPS (Re-LPS) membranes by forming calcium-dependent protein-lipid aggregates on the membrane surface that extract LPS molecules from the membrane, decreasing van der Waals interactions between acyl chains and rendering the membrane leaky; coexistence of gel and fluid lipid phases in the LPS membrane is required for susceptibility to SP-A permeabilization.\",\n      \"method\": \"Epifluorescence microscopy of TR-SP-A on Re-LPS films, monolayer relaxation experiments, differential scanning calorimetry, membrane permeability assay\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biophysical reconstitution with multiple complementary methods (microscopy, monolayer thermodynamics, DSC); single rigorous study establishing mechanism\",\n      \"pmids\": [\"18599636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"P63/CKAP4 functions as a receptor for SP-A on alveolar type II cells and mediates SP-A-dependent surfactant clearance; SP-A null mice deficient in clathrin-dependent uptake use an actin-mediated pathway; administration of SP-A to SP-A-null mice rescues the phenotype.\",\n      \"method\": \"SP-A receptor identification, SP-A gene-targeted mice, SP-A rescue experiment, pharmacological pathway analysis (clathrin vs. actin pathways) — review citing original experimental work\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor identified and rescue experiment described; this is a review citing original data; lower confidence due to indirect access via review abstract\",\n      \"pmids\": [\"20054143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"Phorbol ester (TPA) inhibits SP-A synthesis by decreasing de novo SP-A synthesis and SP-A mRNA levels in a time- and dose-dependent manner; the effect requires continued gene transcription and is not mediated solely by changes in SP-A transcription; actinomycin D blocks the rapid TPA-induced mRNA decrease, suggesting involvement of a labile destabilizing RNA species.\",\n      \"method\": \"35S-methionine incorporation in H441-4 adenocarcinoma cells, SP-A mRNA Northern blot, actinomycin D RNA stability assay, dose-response and kinetics of inhibition\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — metabolic labeling and mRNA stability assays with specific inhibitor controls; single lab\",\n      \"pmids\": [\"2249989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Glucocorticoid inhibition of SP-A is receptor-mediated (blocked by RU 486), involves induction of a labile protein that decreases SP-A gene transcription (~60% reduction) and transiently reduces SP-A mRNA stability (t1/2 ~3 h initially vs ~8 h at steady state); the dominant response to glucocorticoid in fetal human lung is inhibition of SP-A mRNA.\",\n      \"method\": \"Human fetal lung explant culture with dexamethasone, nuclear elongation transcription assay, mRNA stability by actinomycin D and label-chase, cycloheximide, RU 486 blocking\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — nuclear run-on transcription assay plus mRNA stability measurement plus receptor-specificity (RU 486) and protein synthesis (cycloheximide) controls; multiple orthogonal methods\",\n      \"pmids\": [\"8460712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Phorbol ester (TPA) acts primarily at the level of gene transcription to down-regulate SP-A in both H441 cells and human fetal lung explants, reducing SP-A gene transcription rate to ~28% of control.\",\n      \"method\": \"Nuclear elongation assay (run-on transcription), mRNA quantification, dose-response in H441 cells and human fetal lung explants\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — nuclear run-on transcription assay in two model systems; single lab\",\n      \"pmids\": [\"9294011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"SP-A1 and SP-A2 genes are differentially regulated: cAMP preferentially increases SP-A2 mRNA (~5-fold) over SP-A1 mRNA (~2-fold) in human fetal lung, while dexamethasone inhibits SP-A1 and SP-A2 equally (~70%); in H441 cells, dexamethasone inhibits SP-A1 but not SP-A2 mRNA, and cAMP increases both equally.\",\n      \"method\": \"Primer extension analysis of SP-A1 and SP-A2 mRNA in human fetal lung explants and H441 cells treated with DBcAMP, dexamethasone, and insulin\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gene-specific primer extension with multiple hormonal treatments in two model systems; single lab\",\n      \"pmids\": [\"8179013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A germline heterozygous missense mutation in SFTPA1 (p.Trp211Arg) located in the carbohydrate recognition domain impairs SP-A1 secretion, as demonstrated by functional studies; immunohistochemistry shows altered SP-A expression pattern in patient alveolar epithelium; this mutation segregates with IIP/IPF and lung adenocarcinoma.\",\n      \"method\": \"Germline mutation identification, in vitro functional secretion assay (cell transfection), immunohistochemistry on patient lung tissue\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro secretion assay with disease-associated mutation plus patient tissue validation; single lab\",\n      \"pmids\": [\"26792177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A homozygous missense mutation in SFTPA1 disturbs SP-A1 protein secretion and causes IPF via necroptosis of alveolar epithelial type II cells; the cellular mechanism involves phosphorylation of IRE1α leading to JNK-mediated upregulation of RIPK3; JNK inhibition ameliorates pulmonary fibrosis in knock-in mice, and RIPK3 overexpression reverses this protection.\",\n      \"method\": \"Sftpa1 knock-in (KI) mice carrying patient mutation, secretion assay, IRE1α phosphorylation, JNK inhibitor treatment, RIPK3 overexpression, lung histology, influenza challenge\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knock-in mouse model with pathway dissection (JNK inhibitor rescue + RIPK3 genetic overexpression reversal), multiple mechanistic readouts; single lab with rigorous genetic and pharmacological controls\",\n      \"pmids\": [\"31601679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Pathogenic SFTPA1 (and SFTPA2) mutations preserve protein production but abolish secretion; this secretion defect is the shared functional consequence of 11 distinct mutations tested in vitro; SP-A expression pattern is altered in lung tissue of patients carrying these mutations.\",\n      \"method\": \"In vitro expression and secretion assay for 11 SFTPA1/SFTPA2 mutations in cell models, ex vivo immunostaining of patient lung tissue\",\n      \"journal\": \"The European respiratory journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — systematic functional assessment of 11 independent mutations with consistent result (secretion abolished, production preserved); in vitro + ex vivo corroboration; single lab but broad mutation panel\",\n      \"pmids\": [\"32855221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Human SP-A1 allows pulmonary surfactant to achieve lower surface tension after adsorption and during compression-expansion cycling than surfactant with SP-A2 alone or no SP-A; SP-A1 also confers greater resistance to serum inhibition of surfactant function than equivalent amounts of SP-A2.\",\n      \"method\": \"Captive bubble surfactometer assay of humanized transgenic mouse surfactant (expressing SP-A1, SP-A2, or both), reconstituted porcine hydrophobic surfactant with recombinant SP-A1 or SP-A2 added\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biophysical reconstitution assay with both transgenic and recombinant protein approach; single lab\",\n      \"pmids\": [\"27508436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SP-A is produced by human endometrium/decidua and selectively inhibits prostaglandin F2α (PGF2α) production by term decidual stromal cells at a post-transcriptional level without affecting other inflammatory mediators; decidual SP-A expression decreases with labor onset.\",\n      \"method\": \"Immunohistochemistry and RT-PCR for SP-A localization, isolated decidual stromal cell culture with SP-A treatment, ELISA for PGF2α and other mediators, RT-PCR for eicosanoid gene expression\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assay in primary human cells with post-transcriptional mechanism established (protein affected without gene expression change); single lab\",\n      \"pmids\": [\"21270323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"SP-A does not stimulate endocytosis of lipid vesicles by type II cells or MLE-12 cells but does cause surface aggregation of lipid; SP-B and SP-C stimulate lipid endocytosis, with SP-C being most potent; SP-A's role in surfactant recycling is thus distinct from SP-B and SP-C.\",\n      \"method\": \"Fluorescently labeled lipid vesicle binding and endocytosis assay at 4°C and 37°C in rat type II cells and MLE-12 cells with purified SP-A, SP-B, SP-C\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct lipid uptake assay distinguishing SP-A from SP-B/C roles; single lab\",\n      \"pmids\": [\"8772529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SP-A has a bacteriostatic effect on Mycoplasma pneumoniae by binding surface disaturated phosphatidylglycerols and the Mp membrane protein MPN372; SP-A deficiency leads to exaggerated inflammatory responses (TNF-α-driven) and more severe physiological consequences after Mp infection in mice.\",\n      \"method\": \"SP-A -/- vs. wild-type mouse infection with M. pneumoniae, airway hyperresponsiveness measurement, BAL cytokine analysis, pharmacological TNF-α inhibition\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with pharmacological pathway rescue (TNF-α inhibitor); direct binding to M. pneumoniae ligands described; single lab\",\n      \"pmids\": [\"19494306\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SFTPA1-encoded SP-A1 is a calcium-dependent C-type lectin (collectin) that assembles into oligomers dependent on an intact collagenous domain; it specifically binds DPPC and other surfactant phospholipids through its carbohydrate recognition domain (CRD), is required for tubular myelin formation in vivo (a function that requires both SP-A1 and SP-A2 gene products), and is trafficked intracellularly via the endosomal system to lamellar bodies then recycled to the cell surface in a receptor-mediated (BP55/P63-CKAP4-dependent) manner; in innate immunity it acts as an opsonin by binding mannose-containing microbial ligands (bacterial capsular polysaccharides, mycobacterial cell-wall proteins, viral neuraminidase) and bridging pathogens to macrophage SP-A receptors (SPR210) to enhance phagocytosis, while also directly permeabilizing bacterial LPS membranes by forming protein-lipid aggregates; secretion of SP-A1 requires hydroxylation of its collagenous domain, and disease-causing missense mutations in the CRD abolish secretion and trigger necroptosis of alveolar type II cells via an IRE1α→JNK→RIPK3 pathway leading to pulmonary fibrosis; SP-A expression is regulated transcriptionally by cAMP (stimulatory), glucocorticoids (inhibitory, receptor-mediated, requiring new protein synthesis), and protein kinase C/phorbol esters (inhibitory at the transcriptional level), and its function is inactivated by peroxynitrite-mediated nitration of CRD tyrosines.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SFTPA1 encodes SP-A1, a calcium-dependent C-type lectin (collectin) that operates at the interface of pulmonary surfactant homeostasis and innate immune defense [#0, #24]. The protein assembles into large disulfide-bonded oligomers built on a collagen-like triple helix, and both oligomerization and downstream carbohydrate processing depend on an intact collagenous domain [#1]; its C-terminal carbohydrate recognition domain (CRD) carries the higher-affinity calcium-binding site whose occupancy drives the conformational change and reversible aggregation underlying surfactant organization [#2]. SP-A1 specifically binds DPPC and surfactant phospholipids through a mechanism requiring both the diacylglycerol moiety and the phosphocholine head group [#0], enhances phospholipid adsorption and lowers surface tension at the air-liquid interface [#5, #40], and is genetically required \\u2014 together with SP-A2 \\u2014 for tubular myelin formation in vivo [#10, #27]. Secretion requires hydroxylation of the collagenous domain, without which high-mannose precursors accumulate intracellularly [#3], and the protein traffics through an EEA1-positive early endosome before being recycled to the cell surface via Rab4 vesicles while surfactant lipid is diverted to Rab7/CD63 lamellar-body compartments [#19], with P63/CKAP4 (and the SP-A-binding protein BP55) acting as the type II cell receptor for this clearance pathway [#18, #32]. In innate immunity SP-A1 functions as a calcium- and mannose-dependent opsonin, binding bacterial capsular polysaccharides, a 60-kDa mycobacterial cell-wall protein, and influenza neuraminidase, and bridging pathogens to macrophage receptors including the 210-kDa SPR210 to enhance phagocytosis and clearance [#11, #12, #13, #14]; it can also directly permeabilize LPS membranes by extracting LPS into calcium-dependent protein-lipid aggregates [#31], and it restrains TLR-driven inflammation through a TLR2-dependent mechanism [#30]. SP-A function is abolished by peroxynitrite-mediated nitration of CRD tyrosines and by neutrophil serine protease degradation [#15, #20]. Disease-causing missense mutations in the CRD abolish secretion while preserving protein production, and this secretory block triggers necroptosis of alveolar type II cells via an IRE1\\u03b1\\u2192JNK\\u2192RIPK3 pathway, causing idiopathic pulmonary fibrosis [#37, #38, #39].\",\n  \"teleology\": [\n    {\n      \"year\": 1989,\n      \"claim\": \"Established the structural basis of SP-A assembly, defining it as a collagenous oligomeric protein whose higher-order organization and calcium-dependent aggregation depend on an intact collagen-like domain.\",\n      \"evidence\": \"Collagenase digestion, circular dichroism, thermal denaturation, and disulfide mapping of purified SP-A\",\n      \"pmids\": [\"2610270\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No atomic-resolution structure of the oligomer\", \"Stoichiometry of physiological oligomers not defined\"]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"Localized calcium binding to the CRD and linked calcium-induced conformational change to the reversible aggregation underlying surfactant organization, connecting a metal-binding event to function.\",\n      \"evidence\": \"Equilibrium dialysis, limited proteolysis fragments, and intrinsic fluorescence of SP-A\",\n      \"pmids\": [\"2271565\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural detail of the calcium-induced conformational change unresolved\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Defined the lipid-binding specificity of SP-A, showing it recognizes DPPC via both acyl and head-group features and that the collagenous (not glycan) domain is required, mechanistically distinguishing lipid binding from lectin activity.\",\n      \"evidence\": \"125I-SP-A thin-layer chromatogram overlay binding assays with domain-deletion and chemical variants\",\n      \"pmids\": [\"1993679\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how lipid and carbohydrate binding are coordinated in vivo\"]\n    },\n    {\n      \"year\": 1988,\n      \"claim\": \"Showed that collagenous-domain hydroxylation gates intracellular transport and secretion, establishing a post-translational checkpoint for SP-A maturation.\",\n      \"evidence\": \"Metabolic labeling and subcellular fractionation of primary type II cells with prolyl-hydroxylation inhibitors\",\n      \"pmids\": [\"3355864\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the trafficking receptor or quality-control machinery\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Demonstrated receptor-mediated endocytic recycling of SP-A into lamellar bodies by type II cells, framing SP-A as a recycled component of surfactant homeostasis.\",\n      \"evidence\": \"Electron microscopy of SP-A-colloidal gold conjugates with competitive inhibition in rat type II cells\",\n      \"pmids\": [\"8417113\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor identity not established at this stage\", \"Single-lab EM-based readout\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Identified BP55 as a functional type II-cell receptor mediating SP-A-dependent, ATP-dependent lipid uptake to a non-degrading compartment, providing the first molecular handle on the recycling receptor.\",\n      \"evidence\": \"Liposome uptake assay in rat type II cells with anti-BP55 antibody inhibition and ATP/temperature dependence\",\n      \"pmids\": [\"8843792\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular identity of BP55 not cloned here\", \"Single antibody-based inhibition\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Resolved that SP-A and surfactant lipid share an early endosome but then diverge \\u2014 SP-A recycles via Rab4 vesicles while lipid routes to lamellar bodies \\u2014 clarifying that SP-A is recycled rather than co-trafficked with its cargo.\",\n      \"evidence\": \"Immunofluorescence with endosomal markers plus bafilomycin and calmodulin inhibitors in rat type II cells\",\n      \"pmids\": [\"11435209\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not name the receptor driving the divergence\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Named P63/CKAP4 as the SP-A receptor on type II cells mediating surfactant clearance, connecting recycling to a defined protein and rescuable phenotype.\",\n      \"evidence\": \"Receptor identification and SP-A rescue in SP-A-null mice (review citing original work)\",\n      \"pmids\": [\"20054143\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Accessed via review\", \"Relationship between P63/CKAP4 and BP55 not reconciled in timeline\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"A null mouse demonstrated that SP-A is specifically required for tubular myelin assembly while being dispensable for bulk surfactant pool size and lung mechanics, isolating its in vivo structural role.\",\n      \"evidence\": \"Homologous-recombination SP-A knockout with EM, lipid analysis, and lung function measurements\",\n      \"pmids\": [\"8790375\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of tubular myelin assembly not defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed that tubular myelin formation requires both SP-A1 and SP-A2 gene products together, establishing functional non-redundancy between the two paralogs in vivo.\",\n      \"evidence\": \"Humanized SP-A1-only and SP-A2-only transgenic mice with EM and exogenous SP-A rescue, corroborated in human BAL\",\n      \"pmids\": [\"20048345\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometric/structural basis for the SP-A1/SP-A2 requirement not resolved\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Established SP-A as a mannose-dependent calcium-dependent opsonin recognizing diverse microbial ligands, defining its lectin-based innate-immune mechanism.\",\n      \"evidence\": \"Influenza saturation binding, hemagglutination inhibition, and ligand-blot identification of viral neuraminidase\",\n      \"pmids\": [\"7998980\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not test in vivo consequence at this stage\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Extended opsonic recognition to bacterial and mycobacterial ligands and identified the 210-kDa macrophage SP-A receptor (SPR210) bridging pathogens to phagocytes.\",\n      \"evidence\": \"Binding and phagocytosis/killing assays for Klebsiella polysaccharide, M. tuberculosis 60-kDa protein, and BCG with anti-SPR210 blocking\",\n      \"pmids\": [\"9124386\", \"9271309\", \"9176265\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SPR210 molecular identity and signaling not fully defined\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Genetic knockout confirmed in vivo that SP-A is required for efficient bacterial clearance, validating its opsonic role at the organismal level.\",\n      \"evidence\": \"Intratracheal bacterial challenge of SP-A-/- mice with clearance and tubular myelin readouts\",\n      \"pmids\": [\"9813377\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not dissect macrophage signaling downstream of opsonization\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstrated, with knockout and rescue, that SP-A both promotes viral clearance and restrains lung inflammation, showing a dual antimicrobial and immunomodulatory function in vivo.\",\n      \"evidence\": \"IAV and adenovirus infection of SP-A-/- mice with SP-A rescue and cytokine/clearance readouts\",\n      \"pmids\": [\"11839553\", \"10484466\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the receptor mediating the anti-inflammatory effect\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined a TLR2-dependent anti-inflammatory mechanism, showing SP-A suppresses TLR-ligand-induced cytokines and preterm delivery through a specific receptor pathway.\",\n      \"evidence\": \"Cytokine assays in TLR2/TLR4 knockout macrophages and an in vivo preterm-delivery model\",\n      \"pmids\": [\"23700442\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct SP-A/TLR2 physical interaction not shown\", \"Mechanism for non-TLR2 ligands unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Revealed a direct, non-opsonic bactericidal mechanism whereby SP-A permeabilizes LPS membranes by extracting lipid into calcium-dependent protein-lipid aggregates.\",\n      \"evidence\": \"Epifluorescence microscopy, monolayer relaxation, and DSC on Re-LPS films with SP-A\",\n      \"pmids\": [\"18599636\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of direct permeabilization vs opsonization not quantified\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Showed SP-A function is inactivated by peroxynitrite nitration of CRD tyrosines, linking oxidative/nitrosative stress to loss of surfactant and immune activity.\",\n      \"evidence\": \"Peroxynitrite exposure with nitrotyrosine quantification and lipid-aggregation/mannose-binding assays with scavenger controls\",\n      \"pmids\": [\"8806782\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo extent of nitration during disease not established here\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified neutrophil serine proteases as efficient inactivators of SP-A in inflamed (cystic fibrosis) airways, providing a disease-relevant degradation mechanism.\",\n      \"evidence\": \"In vitro protease degradation of purified and native BAL SP-A with inhibitor controls\",\n      \"pmids\": [\"15047952\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of degradation in patients not directly measured\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Established hormonal and gene-specific transcriptional control of SP-A, with cAMP stimulatory and glucocorticoids/phorbol esters inhibitory, defining regulatory inputs.\",\n      \"evidence\": \"Primer extension, nuclear run-on transcription, and mRNA stability assays in fetal lung explants and H441 cells with RU486/cycloheximide controls\",\n      \"pmids\": [\"8179013\", \"8460712\", \"2249989\", \"9294011\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific transcription factors and labile mediators not identified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linked SFTPA1 CRD missense mutations to impaired secretion and familial pulmonary fibrosis, establishing SFTPA1 as a Mendelian disease gene.\",\n      \"evidence\": \"Germline mutation identification, in vitro secretion assay, and patient lung immunohistochemistry\",\n      \"pmids\": [\"26792177\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular death mechanism not yet defined at this stage\", \"Single-family/single-lab functional assay\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the cellular pathomechanism of mutant SP-A1, showing that secretion failure triggers type II-cell necroptosis through IRE1\\u03b1\\u2192JNK\\u2192RIPK3, with genetic and pharmacological rescue establishing causality.\",\n      \"evidence\": \"Sftpa1 knock-in mice with IRE1\\u03b1/JNK/RIPK3 dissection, JNK inhibitor rescue, and RIPK3 overexpression reversal\",\n      \"pmids\": [\"31601679\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism connecting retained protein to IRE1\\u03b1 activation not fully resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Generalized the disease mechanism by showing that 11 distinct SFTPA1/SFTPA2 mutations share a common abolition of secretion with preserved production, defining a unified molecular signature of pathogenicity.\",\n      \"evidence\": \"Systematic in vitro expression/secretion assays for 11 mutations with ex vivo patient tissue immunostaining\",\n      \"pmids\": [\"32855221\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether all mutations converge on the same necroptotic pathway not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SP-A1 oligomers physically template tubular myelin in cooperation with SP-A2, and how the retained mutant protein activates the IRE1\\u03b1 ER-stress sensor, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of the tubular-myelin lattice\", \"Molecular link between secretion block and IRE1\\u03b1 activation undefined\", \"Reconciliation of BP55, P63/CKAP4, and SPR210 receptor identities incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 5, 31]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [11, 12, 13, 14]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [30, 41]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [3, 5, 24]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [9, 19]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [11, 24, 25, 30]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [9, 19, 18]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [38]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SFTPA2\", \"CKAP4\", \"TLR2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}