Affinage

SFTPA1

Pulmonary surfactant-associated protein A1 · UniProt Q8IWL2

Length
248 aa
Mass
26.2 kDa
Annotated
2026-04-28
100 papers in source corpus 35 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SFTPA1 encodes surfactant protein A1 (SP-A1), a collagen-containing C-type lectin (collectin) that is central to pulmonary surfactant homeostasis and innate immune defense in the alveolar space. SP-A1 oligomerizes via its collagen-like domain and intermolecular disulfide bonds, binds calcium-dependently to mannose-containing pathogen surfaces through its carbohydrate recognition domain (CRD) to opsonize bacteria and viruses and directly permeabilize microbial membranes, while its collagen-like domain engages receptors (CKAP4/P63, BP55) on alveolar macrophages and type II pneumocytes to drive clathrin-mediated surfactant endocytosis, suppress the respiratory burst and pro-inflammatory cytokines, and modulate adaptive immunity via IL-10/TGF-β1 (PMID:2610270, PMID:1988071, PMID:9124386, PMID:18599636, PMID:20054143, PMID:18443188, PMID:2171995). SP-A1 cooperates non-redundantly with SP-A2 for tubular myelin formation and provides superior biophysical surfactant film properties including lower minimum surface tension and resistance to serum inhibition (PMID:20048345, PMID:27508436). Pathogenic missense mutations in the SFTPA1 CRD abolish protein secretion while preserving production, triggering ER stress, IRE1α–JNK–RIPK3-mediated necroptosis of alveolar type II cells, and causing familial interstitial pulmonary fibrosis and lung adenocarcinoma (PMID:26792177, PMID:31601679, PMID:32855221).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1989 High

    Establishing how SP-A oligomerizes revealed that the collagen-like domain is essential for higher-order assembly and that CRD cysteines form intramolecular disulfide bonds stabilizing the globular head, defining the basic structural architecture of the protein.

    Evidence Collagenase digestion, circular dichroism, and recombinant expression/mutagenesis in transfected fibroblasts

    PMID:2610270

    Open questions at the time
    • Three-dimensional atomic structure of SP-A1 oligomer not determined
    • Relative contributions of individual cysteines to folding versus function not dissected
  2. 1991 High

    Demonstrating that both the collagen triple helix and the intermolecular disulfide at Cys-9 are required for calcium-dependent phospholipid aggregation established the structural prerequisites for SP-A's surfactant organizing activity, while the C-terminal globular domain was shown to nucleate folding and be required for secretion.

    Evidence Light scattering aggregation assay with DTT reduction and collagenase treatment; deletion mutagenesis with secretion assay in COS cells

    PMID:1712301 PMID:1988071

    Open questions at the time
    • Precise lipid-binding site on the CRD not mapped
    • Whether SP-A1 and SP-A2 differ in phospholipid aggregation not addressed
  3. 1992 High

    Identifying saturable, collagen-domain-mediated binding of SP-A to alveolar macrophages and demonstrating calcium-dependent enhancement of surfactant adsorption to the air-water interface established SP-A's dual role as an immune receptor ligand and biophysical surfactant organizer.

    Evidence 125I-SP-A binding with domain-specific competitive displacement on macrophages; captive bubble surfactometry with SP-A supplementation

    PMID:1314502 PMID:1514646

    Open questions at the time
    • Molecular identity of the macrophage SP-A receptor not yet known
    • Whether the biophysical and receptor-binding activities are coordinated in vivo unclear
  4. 1994 High

    Demonstrating that SP-A binds influenza neuraminidase via its lectin domain and modulates cytokine secretion (GM-CSF) from alveolar cells established SP-A as both a pattern-recognition receptor for viruses and a regulator of innate immune signaling.

    Evidence Saturable binding/ligand blot with influenza A/X31; CFU-C myeloid progenitor assay with antibody neutralization in rat alveolar cells

    PMID:7998980 PMID:8141310

    Open questions at the time
    • Downstream signaling pathway from SP-A to cytokine secretion not identified
    • Whether binding to neuraminidase neutralizes viral infectivity in vivo not tested
  5. 1996 Medium

    Identification of BP55 as a type II pneumocyte receptor mediating SP-A-dependent lipid uptake, along with evidence for energy-dependent receptor-mediated endocytosis, defined the cellular machinery for SP-A-directed surfactant recycling.

    Evidence Temperature/ATP-depletion uptake assay and anti-BP55 antibody inhibition in freshly isolated rat type II cells

    PMID:8843792

    Open questions at the time
    • Molecular cloning and full characterization of BP55 not completed
    • Relative contribution of BP55 versus other candidate receptors not established
  6. 1998 High

    SP-A knockout mice lacking tubular myelin and showing impaired bacterial clearance provided definitive genetic evidence that SP-A is essential for both surfactant ultrastructure and innate pulmonary defense, while suppression of the respiratory burst via the collagen domain revealed an anti-inflammatory function.

    Evidence SP-A−/− mice with EM, bacterial clearance assays, biophysical surfactant analysis; lucigenin chemiluminescence with collagenase-treated SP-A

    PMID:2171995 PMID:9700084 PMID:9813377

    Open questions at the time
    • Relative roles of SP-A1 vs. SP-A2 not resolved in murine single-gene KO
    • Signaling pathway downstream of collagen-domain receptor engagement unknown
  7. 2001 High

    Tracing SP-A trafficking through EEA1→Rab4 recycling vesicles in type II cells, while lipid proceeded to Rab7/lamellar bodies, revealed that SP-A and surfactant lipid are sorted into distinct endosomal pathways after co-internalization, explaining how SP-A is recycled for repeated use.

    Evidence Immunofluorescence with endosomal markers and pharmacological inhibitors (bafilomycin A1, calmodulin inhibitor) in isolated rat type II cells; clathrin/PI3K/PKC inhibitor dissection in macrophages

    PMID:10893207 PMID:11435209

    Open questions at the time
    • Sorting signal on SP-A that directs it to Rab4 vesicles not identified
    • Whether SP-A recycling differs between type II cells and macrophages not compared directly
  8. 2005 High

    Genetic separation of SP-A's bactericidal (membrane permeabilization) and opsonic activities using bacterial mutant screens established that SP-A kills bacteria through direct membrane disruption mechanistically distinct from phagocytosis enhancement.

    Evidence Signature-tagged mutagenesis of P. aeruginosa in SP-A+/+ vs. SP-A−/− mice with in vitro permeabilization assays

    PMID:16322768

    Open questions at the time
    • Structural basis for SP-A insertion into bacterial membranes not resolved
    • Whether SP-A1 and SP-A2 differ in membrane permeabilization not tested
  9. 2008 High

    Biophysical visualization of SP-A forming calcium-dependent aggregates on LPS surfaces that extract LPS molecules defined the physical mechanism of membrane permeabilization, while identification of SP-R210-mediated adaptive immune suppression via IL-10/TGF-β1 extended SP-A's role to T cell regulation.

    Evidence Epifluorescence on LPS films, DSC, vesicle leakage; antibody cross-linking of SP-R210 on PBMC with cytokine ELISA and neutralization

    PMID:18443188 PMID:18599636

    Open questions at the time
    • Whether SP-R210-mediated immunosuppression operates in vivo during infection not shown
    • Stoichiometry of SP-A aggregates on bacterial surfaces unknown
  10. 2010 High

    Humanized transgenic mice proved SP-A1 and SP-A2 are both required for tubular myelin formation and are functionally non-redundant, while SP-A1 was shown to confer superior biophysical surfactant properties including lower surface tension and inhibition resistance.

    Evidence Transgenic mice expressing SP-A1, SP-A2, or both on SP-A KO background; EM; captive bubble surfactometry; human BAL validation

    PMID:20048345 PMID:27508436

    Open questions at the time
    • Structural basis for SP-A1 vs. SP-A2 functional divergence not determined at atomic level
    • Whether specific SP-A1 variants differ in biophysical activity not tested
  11. 2016 High

    Discovery that a CRD missense mutation (p.Trp211Arg) in SFTPA1 abolishes secretion while preserving production, causing familial IPF and lung adenocarcinoma, established SFTPA1 as a Mendelian disease gene and linked its pathogenesis to protein misfolding rather than loss of extracellular function alone.

    Evidence Whole-family genetic segregation analysis; in vitro mutant secretion assay; patient lung immunohistochemistry

    PMID:26792177

    Open questions at the time
    • Whether retained mutant protein triggers ER stress not yet demonstrated
    • Mechanism linking SFTPA1 mutation to lung cancer not elucidated
  12. 2019 High

    Demonstration that secretion-defective SFTPA1 mutations cause ER stress → IRE1α phosphorylation → JNK activation → RIPK3-mediated necroptosis of type II cells, with JNK inhibition rescuing fibrosis in knock-in mice, defined the intracellular pathogenic cascade from misfolded SP-A1 to pulmonary fibrosis.

    Evidence Knock-in mouse with patient SFTPA1 mutation; immunoblotting for IRE1α/JNK/RIPK3; JNK inhibitor rescue; RIPK3 overexpression

    PMID:31601679

    Open questions at the time
    • Whether all 11 known pathogenic mutations converge on the same IRE1α-JNK-RIPK3 axis not tested
    • Role of necroptosis versus apoptosis in human patient lungs not confirmed
  13. 2020 High

    Systematic testing of 11 distinct SFTPA1/SFTPA2 mutations from 14 families confirmed a unifying secretion-null phenotype across all pathogenic variants, consolidating the gain-of-toxic-function disease model.

    Evidence Parallel in vitro mutant expression/secretion assays; ex vivo immunostaining of patient lung biopsies

    PMID:32855221

    Open questions at the time
    • Whether partial secretion rescue could be therapeutic not explored
    • Genotype-phenotype correlations across variants not fully resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • The atomic structure of SP-A1 oligomers, the precise sorting signals that direct SP-A1 recycling versus degradation, the mechanism by which SFTPA1 mutations promote lung adenocarcinoma, and whether therapeutic chaperones can rescue mutant SP-A1 secretion remain unresolved.
  • No high-resolution structure of full-length SP-A1 oligomer
  • Mechanism linking SFTPA1 mutations to lung cancer not defined
  • Whether pharmacological chaperones can restore mutant secretion not tested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0005198 structural molecule activity 3 GO:0008289 lipid binding 3 GO:0048018 receptor ligand activity 3
Localization
GO:0005576 extracellular region 3 GO:0005768 endosome 2 GO:0005783 endoplasmic reticulum 2 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-168256 Immune System 8 R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-5357801 Programmed Cell Death 1
Partners
BP55CKAP4RIPK3SP-A2
Complex memberships
Tubular myelin (with SP-A2)

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1989 SP-A is assembled as large oligomers dependent on an intact collagen-like domain; the cysteines in the non-collagen domain form intrachain (intramolecular) disulfide bonds between residues 135-226 and 204-218; the collagen-like triple helix is confirmed by circular dichroism. Collagenase digestion, circular dichroism spectroscopy, recombinant expression in transfected fibroblasts The American journal of physiology High 2610270
1991 SP-A aggregates phospholipid vesicles in a calcium-dependent manner requiring both the quaternary collagen-like triple helix and intermolecular disulfide bond at Cys-9; reduction of the intermolecular disulfide with DTT or collagenase digestion abolishes aggregation and phospholipid binding. Intramolecular bonds are Cys138-Cys229 and Cys207-Cys221. Light scattering aggregation assay, DTT reduction, collagenase digestion, HPLC tryptic peptide analysis, 14C-alkylation Biochemistry High 1988071
1991 The C-terminal non-collagenous (globular) domain of SP-A is essential for correct folding and secretion; deletions in this domain reduce or abolish secretion, suggesting it acts as a nucleation center for collagen triple-helix folding in a zipper-like fashion from C- to N-terminus. Transient expression of deletion mutants in COS cells; secretion assay European journal of biochemistry High 1712301
1992 SP-A binds specifically and saturably to rat alveolar macrophages; binding is mediated through the collagen-like domain of SP-A (blocked by C1q and type V collagen but not albumin), consistent with a specific SP-A receptor on alveolar macrophages. 125I-labeled SP-A binding assay at 4°C with competitive displacement by collagen-domain ligands The American journal of physiology High 1314502
1992 SP-A enhances adsorption of lipid extract surfactant to the air-water interface in a calcium-dependent manner and induces surface sorting (enrichment of DPPC), reducing the need for compression to achieve low surface tensions. Captive bubble surfactometry with varying concentrations and SP-A supplementation The American journal of physiology High 1514646
1993 Glucocorticoid inhibition of SP-A expression is receptor-mediated, involves induction of a labile protein that decreases gene transcription and transiently reduces SP-A mRNA stability; the inhibitory response requires new protein synthesis (blocked by cycloheximide). Nuclear elongation transcription assay, actinomycin D/label-chase mRNA stability assay, RU-486 receptor blockade, cycloheximide treatment in cultured human fetal lung explants The American journal of physiology High 8460712
1993 SP-A is localized by immunogold EM to lamellar bodies, endoplasmic reticulum, and cytoplasmic membrane of type II cells, and to extracellular tubular myelin; SP-A is absent from tubular myelin in RDS lungs, supporting a required role for SP-A in the conversion of lamellar bodies to tubular myelin. Immunogold electron microscopy with affinity-purified anti-SP-A IgG on ultrathin sections of human lung The American journal of pathology Medium 8494055
1994 SP-A binds to influenza virus (strain A/X31) through its lectin (carbohydrate recognition) domain in a calcium-dependent, saturable manner and inhibits hemagglutination; the viral neuraminidase (68 kDa) was identified as the SP-A binding target. Saturable binding assay, ligand blot, neuraminidase isolation and inhibition of SP-A/MBP binding The Biochemical journal High 7998980
1994 SP-A upregulates secretion of GM-CSF and IL-3-like colony-stimulating factors from alveolar type II cells and macrophages in a concentration-dependent manner (0.1–5 µg/ml), but not from control non-lung cells, indicating a cell-type-specific cytokine-regulatory role. In vitro CFU-C myeloid progenitor assay, antibody neutralization in cultured rat alveolar cells The American journal of physiology Medium 8141310
1994 SP-A-mediated surfactant endocytosis by type II pneumocytes is inhibited by monensin (an endocytosis inhibitor), and SP-A accumulates with the lung after monensin treatment, indicating SP-A is cleared from alveolar space partly via an endocytic pathway in alveolar epithelial cells. 125I-SP-A instillation in anesthetized rabbits with pharmacological endocytosis inhibitors (monensin, nocodazole) The American journal of physiology Medium 8203547
1995 SP-A binding to its receptor on alveolar macrophages is inversely regulated relative to the mannose receptor: agents that upregulate macrophage activation (LPS, IFN-γ, PMA) increase SP-A receptor binding while decreasing mannose receptor activity, and vice versa for dexamethasone, suggesting SP-A receptor acts as an inflammation-upregulated opsonin receptor. Competitive binding assays on rat marrow-derived macrophages and alveolar macrophages after pharmacological or in vivo treatment The American journal of physiology Medium 8572233
1995 SP-A with DPPC shows partial miscibility and interaction in mixed monolayers; SP-A is squeezed out at ~30 mN/m but enhances respreading of DPPC films after collapse. SP-A mixes with DPPG only in the presence of calcium ions. Langmuir trough spread monolayer experiments with binary lipid-protein mixtures Biochemistry Medium 7640284
1996 SP-A-mediated lipid uptake by rat type II pneumocytes is an energy- and temperature-dependent, receptor-mediated endocytic process involving the cell surface binding protein BP55; an auto-anti-idiotypic antibody against BP55 inhibits SP-A-mediated liposome uptake. Temperature/ATP-depletion uptake assay, antibody inhibition of BP55 in freshly isolated rat type II cells The American journal of physiology Medium 8843792
1997 SP-A enhances phagocytosis of Klebsiella pneumoniae K21a (containing Manα1-Man capsular sequences) but not K2 by alveolar macrophages via two mechanisms: (1) opsonization by binding mannose-containing capsular polysaccharides through the CRD, and (2) activation of the macrophage mannose receptor; both activities are inhibited by mannan. Agglutination assay, binding of SP-A-coated particles to bacterial surface, macrophage phagocytosis and killing assay, mannan inhibition The American journal of physiology High 9124386
1998 SP-A (-/-) mice have normal surfactant phospholipid composition and lung function under basal conditions but lack tubular myelin figures in the lung and show impaired clearance of Group B streptococci and Pseudomonas aeruginosa, demonstrating SP-A's role in tubular myelin formation and innate lung defense. Gene-targeted SP-A knockout mice; electron microscopy; bacterial clearance assays in vivo Biochimica et biophysica acta High 9813377
1998 SP-A-deficient surfactant has lower buoyant density, decreased large-aggregate forms, increased conversion of large to small aggregates during cycling, increased sensitivity to plasma protein inhibition, and lacks tubular myelin, showing SP-A is required for normal surfactant aggregate structure. Buoyant density centrifugation, surface area cycling, biophysical inhibition assays, electron microscopy in SP-A KO mice The American journal of physiology High 9700084
1998 SP-A suppresses the respiratory burst (superoxide anion production) in bronchoalveolar lavage cells and peripheral neutrophils after PMA stimulation; this inhibitory effect is abolished by prior collagenase treatment of SP-A, implicating the collagen-like domain in this immunosuppressive function. Lucigenin-dependent chemiluminescence assay; collagenase pre-treatment of SP-A FEBS letters Medium 2171995
1999 Glucocorticoid inhibition of the SP-A1 promoter is mediated by a region between -32/+63 relative to the transcription start; sequences within +18/+63 are necessary for dexamethasone responsiveness, and this region forms a sequence-specific DNA-protein complex with nuclear extract that is induced by dexamethasone. Deletional analysis of SP-A1 promoter with reporter gene in NCI-H441 cells; gel mobility shift (EMSA) The Biochemical journal Medium 10229660
1999 SP-A enhances clearance of adenovirus from the lung and reduces adenoviral-induced lung inflammation (decreased TNF-α, IL-6, IL-1β, chemokines); SP-A-/- mice show decreased uptake of adenovirus by alveolar macrophages, restored by exogenous SP-A. Intratracheal infection of SP-A-/- vs. SP-A+/+ mice; BALF cytokine measurement; fluorescent adenovirus uptake assay; exogenous SP-A rescue The American journal of physiology High 10484466
2000 Amiodarone inhibits degradation of SP-A in alveolar macrophages and in vivo in rabbit lungs by disrupting the endocytic pathway after early endosomes and altering trafficking of lysosomal enzymes, without affecting DPPC degradation, indicating SP-A degradation follows a specific clathrin/endosomal route distinct from lipid degradation. In vitro macrophage exposure to amiodarone; SP-A degradation assay; lysosomal enzyme distribution; in vivo tracheal instillation in newborn rabbits American journal of physiology. Lung cellular and molecular physiology Medium 11597911
2001 After endocytosis by rat type II pneumocytes, SP-A and surfactant lipid are initially co-localized in EEA1-positive early endosomes via the coated-pit pathway, then SP-A is rapidly recycled to the cell surface via Rab4-positive vesicles, while lipid is directed to Rab7/CD63/lamellar body compartments; calmodulin inhibition blocks transport out of early endosomes. Immunofluorescence with endosomal markers (EEA1, Rab4, Rab7, CD63), pharmacological inhibitors (bafilomycin A1, calmodulin inhibitor) in isolated rat type II cells American journal of physiology. Lung cellular and molecular physiology High 11435209
2000 SP-A degradation by alveolar macrophages requires clathrin-mediated internalization, an intact cytoskeleton, and an acidic lysosomal milieu; protein kinase C stimulation increases SP-A degradation; PI3K regulates both internalization speed and subsequent intracellular steps. DPPC degradation is unaffected by these treatments, establishing separate degradative pathways. Pharmacological inhibitors of clathrin, cytoskeleton, lysosomal acidification, PKC, and PI3K in rabbit alveolar macrophages; SP-A and DPPC degradation assays American journal of physiology. Lung cellular and molecular physiology Medium 10893207
2002 Absence of SP-A in mice results in decreased influenza A virus clearance, impaired neutrophil myeloperoxidase activity, and skewed adaptive immunity toward increased Th1 responses; exogenous SP-A restores viral clearance and reduces inflammation. Intranasal influenza infection of SP-A-/- and SP-A+/+ mice; BAL myeloperoxidase; lymphocyte/cytokine analysis; exogenous SP-A rescue American journal of physiology. Lung cellular and molecular physiology High 11839553
2003 SP-A is required for increased DPPC clearance in response to CO2-induced hyperventilation or secretagogue treatment; SP-A-/- mice show no increase in DPPC uptake under these stimuli and have increased lysosomal phospholipase A2 activity, suggesting SP-A normally channels surfactant lipid into a receptor-mediated uptake pathway suppressing lysosomal degradation. 3H-DPPC liposome instillation in SP-A-/- vs. SP-A+/+ anesthetized mice; hyperventilation and secretagogue challenge; lysosomal PLA2 activity assay American journal of physiology. Lung cellular and molecular physiology High 12676766
2005 SP-A permeabilizes Pseudomonas aeruginosa membranes; signature-tagged mutagenesis identified bacterial genes for salicylate biosynthesis (pch) and phosphoenolpyruvate-protein phosphotransferase (ptsP) that confer resistance to SP-A-mediated membrane permeabilization but not opsonization, establishing that SP-A's bactericidal and opsonization functions are mechanistically separable. Comparative signature-tagged mutagenesis in SP-A+/+ vs. SP-A-/- mice; in vitro membrane permeabilization assays PLoS pathogens High 16322768
2008 SP-A permeabilizes rough LPS membranes by forming large protein aggregates on the LPS surface (calcium-dependent) that extract LPS molecules from the membrane, reducing van der Waals interactions between acyl chains; coexistence of gel and fluid lipid phases within the LPS membrane is required for susceptibility. Epifluorescence microscopy of labeled SP-A on LPS films, LPS monolayer relaxation at constant pressure, differential scanning calorimetry, lipid vesicle leakage assay Biophysical journal High 18599636
2008 SP-A suppresses T cell-mediated immune responses to Mycobacterium tuberculosis via its receptor SP-R210; antibodies cross-linking SP-R210 through the SP-A-binding (neck) domain markedly inhibit proliferation and IFN-γ while increasing IL-10 and TGF-β1; neutralization of IL-10 and TGF-β1 abrogates the inhibition. Antibody cross-linking of SP-R210 on PBMC; cell proliferation assay; cytokine ELISA; neutralizing antibody rescue experiment Journal of leukocyte biology Medium 18443188
2009 P63/CKAP4 (a 63 kDa transmembrane protein) functions as an SP-A receptor on type II pneumocytes and mediates clathrin-dependent endocytosis of surfactant; SP-A-/- mice use an actin-dependent non-clathrin pathway, and addition of exogenous SP-A rescues the normal clathrin-mediated phenotype. Receptor identification, endocytosis pathway pharmacology, SP-A-/- rescue experiment; reviewed in synthesis paper with primary data Cellular physiology and biochemistry Medium 20054143
2010 Tubular myelin formation in vivo requires both SP-A1 (SFTPA1) and SP-A2 (SFTPA2) gene products; humanized transgenic mice expressing only SP-A1 or only SP-A2 both lack tubular myelin, while mice expressing both have tubular myelin. Human BAL fluid with predominantly a single SP-A gene product also lacks tubular myelin, confirming functional divergence. Humanized transgenic mice (SP-A KO background) expressing SP-A1 or SP-A2 individually or together; electron microscopy; in vivo rescue with exogenous combined SP-A; human BAL analysis The Journal of biological chemistry High 20048345
2010 SFTPA1 3' UTR variants differentially regulate translation efficiency: the 6A3 and 6A4 variants exhibit higher translation efficiency than 6A2 in vitro and in cell transfection; an 11-nucleotide element in the 3' UTR alters predicted mRNA secondary structure and miRNA binding sites, accounting for differential translational regulation. In vitro transcription/translation with luciferase reporter; transient transfection of NCI-H441 cells; 11-nt deletion/insertion mutagenesis; RNA secondary structure prediction American journal of physiology. Lung cellular and molecular physiology Medium 20693318
2016 A germline missense mutation in SFTPA1 (p.Trp211Arg) in the carbohydrate recognition domain impairs SP-A1 secretion while protein production is maintained; this causes familial IPF and lung adenocarcinoma, and SP-A1 and SP-A2 are shown to be non-redundant despite structural similarity. Whole-family genetic analysis, in vitro secretion assay of mutant protein, immunohistochemistry on patient alveolar epithelium Human molecular genetics High 26792177
2016 SP-A1 (encoded by SFTPA1) confers better biophysical surfactant film properties than SP-A2: surfactant containing SP-A1 reaches lower surface tension after post-expansion adsorption, reorganizes better under cycling compression, and provides greater resistance to serum inhibition; these functions are SP-A1-specific. Captive bubble surfactometry on BAL from humanized transgenic mice expressing SP-A1, SP-A2, or both; recombinant SP-A reconstitution with porcine surfactant Biophysical journal High 27508436
2019 A homozygous missense mutation in SFTPA1 causes IPF by impairing SFTPA1 protein secretion, leading to necroptosis of alveolar type II epithelial cells via phosphorylation of IRE1α, JNK-mediated upregulation of Ripk3; JNK inhibition ameliorates pulmonary fibrosis in knock-in mice, and Ripk3 overexpression rescues the fibrotic phenotype. Knock-in mouse model with patient mutation; immunoblotting for IRE1α/JNK/Ripk3 signaling; JNK inhibitor treatment; Ripk3 overexpression rescue; necroptosis assay The Journal of experimental medicine High 31601679
2020 Pathogenic SFTPA1 (and SFTPA2) mutations preserve protein production but abolish secretion in cell models; 11 distinct mutations from 14 unrelated patients all share this secretion-null phenotype, with altered SP-A expression pattern in patient lung tissue. In vitro mutant protein expression and secretion assay; ex vivo SP-A immunostaining in patient lung biopsy The European respiratory journal High 32855221
2022 SP-A deficiency (CRISPR/Cas9-mediated) exacerbates bleomycin-induced pulmonary fibrosis; in vitro, TGF-β1 decreases SP-A protein expression in lung epithelial cells, and exogenous SP-A inhibits TGF-β1-induced upregulation of fibrotic markers, establishing an antifibrotic function of SP-A. CRISPR/Cas9 SP-A KO mouse + bleomycin model; in vitro TGF-β1 treatment of LA-4 cells; exogenous SP-A rescue; Western blotting for fibrotic markers International journal of molecular sciences Medium 35628104

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Surfactant proteins SP-A and SP-D: structure, function and receptors. Molecular immunology 410 16213021
2005 The lung collectins, SP-A and SP-D, modulate pulmonary innate immunity. Molecular immunology 154 15589315
2005 Echinococcus shiquicus n. sp., a taeniid cestode from Tibetan fox and plateau pika in China. International journal for parasitology 132 15862582
2002 Absence of SP-A modulates innate and adaptive defense responses to pulmonary influenza infection. American journal of physiology. Lung cellular and molecular physiology 114 11839553
2021 SP-A and SP-D: Dual Functioning Immune Molecules With Antiviral and Immunomodulatory Properties. Frontiers in immunology 113 33542724
2013 Blood biomarkers MMP-7 and SP-A: predictors of outcome in idiopathic pulmonary fibrosis. Chest 113 23715088
1992 Pulmonary SP-A enhances adsorption and appears to induce surface sorting of lipid extract surfactant. The American journal of physiology 113 1514646
2016 Germline SFTPA1 mutation in familial idiopathic interstitial pneumonia and lung cancer. Human molecular genetics 109 26792177
1992 Specific binding of surfactant apoprotein SP-A to rat alveolar macrophages. The American journal of physiology 106 1314502
1997 SP-A enhances phagocytosis of Klebsiella by interaction with capsular polysaccharides and alveolar macrophages. The American journal of physiology 102 9124386
2001 Surfactant protein A (SP-A): the alveolus and beyond. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 92 11149893
2003 Ostreopsis sp., a possible origin of palytoxin (PTX) in parrotfish Scarus ovifrons. Toxicon : official journal of the International Society on Toxinology 89 12893058
1998 Surfactant protein A (SP-A) gene targeted mice. Biochimica et biophysica acta 89 9813377
1989 Studies of the structure of lung surfactant protein SP-A. The American journal of physiology 81 2610270
1998 Brachiola vesicularum, n. g., n. sp., a new microsporidium associated with AIDS and myositis. The Journal of eukaryotic microbiology 79 9627985
1998 Characteristics of surfactant from SP-A-deficient mice. The American journal of physiology 75 9700084
1994 Binding of human collectins (SP-A and MBP) to influenza virus. The Biochemical journal 72 7998980
1994 Secretion of cytokines by rat alveolar epithelial cells: possible regulatory role for SP-A. The American journal of physiology 69 8141310
2008 Description of Perkinsus beihaiensis n. sp., a new Perkinsus sp. parasite in oysters of Southern China. The Journal of eukaryotic microbiology 65 18318865
2019 A homozygous SFTPA1 mutation drives necroptosis of type II alveolar epithelial cells in patients with idiopathic pulmonary fibrosis. The Journal of experimental medicine 63 31601679
2010 Humanized SFTPA1 and SFTPA2 transgenic mice reveal functional divergence of SP-A1 and SP-A2: formation of tubular myelin in vivo requires both gene products. The Journal of biological chemistry 63 20048345
2002 FDC-SP, a novel secreted protein expressed by follicular dendritic cells. Journal of immunology (Baltimore, Md. : 1950) 62 12193705
1999 Ultrastructural characterisation and molecular taxonomic identification of Nosema granulosis n. sp., a transovarially transmitted feminising (TTF) microsporidium. The Journal of eukaryotic microbiology 62 10519217
2005 Surfactant proteins SP-A and SP-D in human health and disease. Archivum immunologiae et therapiae experimentalis 60 16314824
2010 Role of surfactant protein A and D (SP-A and SP-D) in human antiviral host defense. Frontiers in bioscience (Scholar edition) 59 20036966
2008 Ablation of SP-A has a negative impact on the susceptibility of mice to Klebsiella pneumoniae infection after ozone exposure: sex differences. Respiratory research 58 19055785
1999 SP-A enhances viral clearance and inhibits inflammation after pulmonary adenoviral infection. The American journal of physiology 58 10484466
1995 Differential regulation of the mannose and SP-A receptors on macrophages. The American journal of physiology 57 8572233
1993 Biphasic glucocorticoid regulation of pulmonary SP-A: characterization of inhibitory process. The American journal of physiology 56 8460712
1993 Immunogold localization of SP-A in lungs of infants dying from respiratory distress syndrome. The American journal of pathology 53 8494055
1995 SP-A deficiency in primate model of bronchopulmonary dysplasia with infection. In situ mRNA and immunostains. American journal of respiratory and critical care medicine 51 7881683
2009 Myxobolus cordeiroi n. sp., a parasite of Zungaro jahu (Siluriformes: Pimelodiade) from Brazilian Pantanal: morphology, phylogeny and histopathology. Veterinary parasitology 50 19372007
1994 Effect of endocytosis inhibitors on alveolar clearance of albumin, immunoglobulin G, and SP-A in rabbits. The American journal of physiology 49 8203547
2016 Surfactant proteins, SP-A and SP-D, in respiratory fungal infections: their role in the inflammatory response. Respiratory research 48 27250970
2001 Localization and functions of SP-A and SP-D at mucosal surfaces. Pediatric pathology & molecular medicine 44 11486736
2016 Human Pulmonary Surfactant Protein SP-A1 Provides Maximal Efficiency of Lung Interfacial Films. Biophysical journal 42 27508436
2018 Genetic Association of Pulmonary Surfactant Protein Genes, SFTPA1, SFTPA2, SFTPB, SFTPC, and SFTPD With Cystic Fibrosis. Frontiers in immunology 40 30333828
2005 Variants of the SFTPA1 and SFTPA2 genes and susceptibility to tuberculosis in Ethiopia. Human genetics 40 16292672
2020 Functional assessment and phenotypic heterogeneity of SFTPA1 and SFTPA2 mutations in interstitial lung diseases and lung cancer. The European respiratory journal 39 32855221
2003 Observations on the life stages of Sphaerothecum destruens n. g., n. sp., a mesomycetozoean fish pathogen formerly referred to as the rosette agent [correction]. The Journal of eukaryotic microbiology 39 14733435
1990 Effect of canine surfactant protein (SP-A) on the respiratory burst of phagocytic cells. FEBS letters 39 2171995
2017 The kinetics and mechanism of α-glucosidase inhibition by F5-SP, a novel compound derived from sericin peptides. Food & function 37 28045172
2013 Ligands and receptors of lung surfactant proteins SP-A and SP-D. Frontiers in bioscience (Landmark edition) 37 23747872
2005 Comparative signature-tagged mutagenesis identifies Pseudomonas factors conferring resistance to the pulmonary collectin SP-A. PLoS pathogens 36 16322768
2018 Differential effects of innate immune variants of surfactant protein-A1 (SFTPA1) and SP-A2 (SFTPA2) in airway function after Klebsiella pneumoniae infection and sex differences. Respiratory research 35 29394894
2004 Modulatory effects of ozone on THP-1 cells in response to SP-A stimulation. American journal of physiology. Lung cellular and molecular physiology 34 15466251
2001 Amiodarone inhibits lung degradation of SP-A and perturbs the distribution of lysosomal enzymes. American journal of physiology. Lung cellular and molecular physiology 32 11597911
1993 Surfactant-associated proteins (SP-A, SP-B) are increased proportionally to alveolar phospholipids in sheep silicosis. Lung 32 8426464
2011 The role of alternate hosts in the ecology and life history of Hematodinium sp., a parasitic dinoflagellate of the blue crab (Callinectes sapidus). The Journal of parasitology 31 21812642
2009 P63 (CKAP4) as an SP-A receptor: implications for surfactant turnover. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 31 20054143
2000 Tolerance of SP-A-deficient mice to hyperoxia or exercise. Journal of applied physiology (Bethesda, Md. : 1985) 30 10926649
1998 Suppressive effects of SP-A on ionomycin-induced IL-8 production and release by eosinophils. International archives of allergy and immunology 30 9758900
1994 Human SP-A: genotype and single-strand conformation polymorphism analysis. The American journal of physiology 30 8203545
1993 Reclinomonas americana N. G., N. Sp., a new freshwater heterotrophic flagellate. The Journal of eukaryotic microbiology 29 8461890
2012 Air pollution and epigenetics: effects on SP-A and innate host defence in the lung. Swiss medical weekly 28 22553125
1996 SP-A-binding protein BP55 is involved in surfactant endocytosis by type II pneumocytes. The American journal of physiology 28 8843792
2019 Resistance towards metronidazole in Blastocystis sp.: A pathogenic consequence. PloS one 27 30794628
2012 Rigifila ramosa n. gen., n. sp., a filose apusozoan with a distinctive pellicle, is related to Micronuclearia. Protist 27 22682062
2008 SP-A permeabilizes lipopolysaccharide membranes by forming protein aggregates that extract lipids from the membrane. Biophysical journal 27 18599636
2003 SP-A is necessary for increased clearance of alveolar DPPC with hyperventilation or secretagogues. American journal of physiology. Lung cellular and molecular physiology 27 12676766
1990 125I-BH[Sar9, Met(O2)11]-SP, a new selective ligand for the NK-1 receptor in the central nervous system. Brain research 27 1705465
2008 An antibody against the surfactant protein A (SP-A)-binding domain of the SP-A receptor inhibits T cell-mediated immune responses to Mycobacterium tuberculosis. Journal of leukocyte biology 26 18443188
2001 Endocytosed SP-A and surfactant lipids are sorted to different organelles in rat type II pneumocytes. American journal of physiology. Lung cellular and molecular physiology 26 11435209
2014 Trichomonas gypaetinii n. sp., a new trichomonad from the upper gastrointestinal tract of scavenging birds of prey. Parasitology research 25 25273632
2011 Tsukubamonas globosa n. gen., n. sp., a novel excavate flagellate possibly holding a key for the early evolution in "Discoba". The Journal of eukaryotic microbiology 25 21569159
2002 Combined SP-A-bleomycin effect on cytokines by THP-1 cells: impact of surfactant lipids on this effect. American journal of physiology. Lung cellular and molecular physiology 25 12060565
2018 Ophirina amphinema n. gen., n. sp., a New Deeply Branching Discobid with Phylogenetic Affinity to Jakobids. Scientific reports 24 30385814
2016 Parahepatospora carcini n. gen., n. sp., a parasite of invasive Carcinus maenas with intermediate features of sporogony between the Enterocytozoon clade and other microsporidia. Journal of invertebrate pathology 22 27993617
2009 Light microscopic observations, ultrastructure, and molecular phylogeny of Hicanonectes teleskopos n. g., n. sp., a deep-branching relative of diplomonads. The Journal of eukaryotic microbiology 22 19602083
2006 Association of common haplotypes of surfactant protein A1 and A2 (SFTPA1 and SFTPA2) genes with severity of lung disease in cystic fibrosis. Pediatric pulmonology 22 16429424
2010 Surfactant protein (SP)-A and SP-D as antimicrobial and immunotherapeutic agents. Recent patents on anti-infective drug discovery 21 20230362
2000 Propionispora vibrioides, nov. gen., nov. sp., a new gram-negative, spore-forming anaerobe that ferments sugar alcohols. Archives of microbiology 21 11081792
1999 Glucocorticoid inhibition of human SP-A1 promoter activity in NCI-H441 cells. The Biochemical journal 21 10229660
1995 Human SP-A: then and now. The American journal of physiology 21 7864137
1991 Assembly of the surfactant protein SP-A. Deletions in the globular domain interfere with the correct folding of the molecule. European journal of biochemistry 21 1712301
2016 Steinernema biddulphi n. sp., a New Entomopathogenic Nematode (Nematoda: Steinernematidae) from South Africa. Journal of nematology 20 27765988
2004 Factors affecting SP-A-mediated phagocytosis in human monocytic cell lines. Respiratory medicine 20 15250230
1995 Pulmonary surfactant protein SP-A with phospholipids in spread monolayers at the air-water interface. Biochemistry 20 7640284
2021 Anteholosticha foissneri n. sp., a marine hypotrich ciliate (Ciliophora: Spirotrichea) from Vietnam: Morphology, morphogenesis, and molecular phylogeny. European journal of protistology 19 33549970
2019 A novel germline mutation of the SFTPA1 gene in familial interstitial pneumonia. Human genome variation 19 30854216
2011 Mataza hastifera n. g., n. sp.: a possible new lineage in the Thecofilosea (Cercozoa). The Journal of eukaryotic microbiology 19 21205061
2010 Differences in the BAL proteome after Klebsiella pneumoniae infection in wild type and SP-A-/- mice. Proteome science 19 20565803
2002 Structural and functional aspects of the collectin SP-A. Immunobiology 19 12396009
2001 Human surfactant protein A (SP-A) variants: why so many, why such a complexity? Swiss medical weekly 19 11416882
1991 Intermolecular cross-links mediate aggregation of phospholipid vesicles by pulmonary surfactant protein SP-A. Biochemistry 19 1988071
2019 Major Effect of Oxidative Stress on the Male, but Not Female, SP-A1 Type II Cell miRNome. Frontiers in immunology 18 31354704
2015 Characterization of Amphora sp., a newly isolated diatom wild strain, potentially usable for biodiesel production. Bioprocess and biosystems engineering 18 25716001
2014 First report of Pseudobodo sp, a new pathogen for a potential energy-producing algae: Chlorella vulgaris cultures. PloS one 18 24599263
2019 Differential Impact of Co-expressed SP-A1/SP-A2 Protein on AM miRNome; Sex Differences. Frontiers in immunology 17 31475015
2013 Genotype-phenotype correlation in Chinese patients with pulmonary mixed type adenocarcinoma: Relationship between histologic subtypes, TITF-1/SP-A expressions and EGFR mutations. Pathology, research and practice 17 24370340
2022 Surfactant Protein-A Function: Knowledge Gained From SP-A Knockout Mice. Frontiers in pediatrics 16 35071140
2014 Genes involved in the endoplasmic reticulum N-glycosylation pathway of the red microalga Porphyridium sp.: a bioinformatic study. International journal of molecular sciences 16 24514561
2014 Pentachlorophenol degradation by Janibacter sp., a new actinobacterium isolated from saline sediment of arid land. BioMed research international 16 25313357
2010 Human SP-A1 (SFTPA1) variant-specific 3' UTRs and poly(A) tail differentially affect the in vitro translation of a reporter gene. American journal of physiology. Lung cellular and molecular physiology 16 20693318
1999 Cloning of the mouse homolog of the 126-kDa human C1q/MBL/SP-A receptor, C1qR(p). Mammalian genome : official journal of the International Mammalian Genome Society 16 10430665
2014 Baylisascaris potosis n. sp., a new ascarid nematode isolated from captive kinkajou, Potos flavus, from the Cooperative Republic of Guyana. Parasitology international 15 24662055
2006 Surfactant dysfunction in SP-A-/- and iNOS-/- mice with mycoplasma infection. American journal of respiratory cell and molecular biology 15 16917077
2001 In situ hybridization of SP-A mRNA in adult human conducting airways. Pediatric pathology & molecular medicine 15 11552737
2000 Different pathways of degradation of SP-A and saturated phosphatidylcholine by alveolar macrophages. American journal of physiology. Lung cellular and molecular physiology 15 10893207
2022 Loss of SP-A in the Lung Exacerbates Pulmonary Fibrosis. International journal of molecular sciences 14 35628104