Ultrastructure of lung in surfactant protein B deficiency.

deMello, Daphne E.; Heyman, Sarah; Phelps, David S.; Hamvas, Aaron; Nogee, Lawrence M.; Cole, Sessions; Colten, Harvey R.

doi:10.1165/ajrcmb.11.2.8049084

Cited by 107 publications

(38 citation statements)

References 37 publications

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“…SP-B appears to be one of the key proteins necessary for the proper organization of lamellar bodies. Newborns with hereditary SP-B deficiency have poorly formed lamellar bodies and abnormal surfactant (20,21). Similar abnormalities have been demonstrated in SP-B-deficient mice (22).…”

supporting

confidence: 69%

Identification of LBM180, a Lamellar Body Limiting Membrane Protein of Alveolar Type II Cells, as the ABC Transporter Protein ABCA3

Mulugeta¹,

Gray²,

Notarfrancesco³

et al. 2002

Journal of Biological Chemistry

200

167

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Lamellar bodies are the specialized secretory organelles of alveolar type II (ATII) epithelial cells through which the cell packages pulmonary surfactant and regulates its secretion. Surfactant within lamellar bodies is densely packed as circular arrays of lipid membranes and appears to be the product of several trafficking and biosynthetic processes. To elucidate these processes, we reported previously on the generation of a monoclonal antibody (3C9) that recognizes a unique protein of the lamellar body membrane of 180 kDa, which we named LBM180. We report that mass spectrometry of the protein precipitated by this antibody generated a partial sequence that is identical to the ATP-binding cassette protein, ABCA3. Homology analysis of partial sequences suggests that this protein is highly conserved among species. The ABCA3 gene transcript was found in cell lines of human lung origin, in ATII cells of human, rat, and mouse, as well as different tissues of rat, but the highest expression of ABCA3 was observed in ATII cells. Expression of this transcript was at its maximum prior to birth, and hormonal induction of ABCA3 transcript was observed in human fetal lung at the same time as other surfactant protein transcripts were induced, suggesting that ABCA3 is developmentally regulated. Molecular and biochemical studies show that ABCA3 is targeted to vesicle membranes and is found in the limiting membrane of lamellar bodies. Because ABCA3 is a member of a subfamily of ABC transporters that are predominantly known to be involved in the regulation of lipid transport and membrane trafficking, we speculate that this protein may play a key role in lipid organization during the formation of lamellar bodies.

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supporting

confidence: 69%

Identification of LBM180, a Lamellar Body Limiting Membrane Protein of Alveolar Type II Cells, as the ABC Transporter Protein ABCA3

Mulugeta¹,

Gray²,

Notarfrancesco³

et al. 2002

Journal of Biological Chemistry

200

167

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“…Mature lamellar bodies are absent in type II pneumocytes in surfactant protein-B deficiency, which features composite bodies with membranous and vesicular structures instead. 14,21 Similarly, deficiency of mature lamellar bodies in alveolar type II cells has been described in ABCA3 mutations. 1,14 In contrast to surfactant protein-B deficiency, in ABCA3 mutations, a different, characteristic phenotype of lamellar bodies has been described.…”

Section: Abca3 In Neonatal Pneumoniamentioning

confidence: 86%

Ultrastructural and molecular analysis in fatal neonatal interstitial pneumonia caused by a novel ABCA3 mutation

et al. 2007

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Pulmonary surfactant is essential to maintain alveolar patency, and invariably fatal neonatal lung disease has been recognized to involve mutations in the genes encoding surfactant protein-B or ATP-binding cassette transporter family member ABCA3. The lipid transporter ABCA3 targets surfactant phospholipids to lamellar bodies that are lysosomal-derived organelles of alveolar type II cells. ABCA3À/À mice have grossly reduced surfactant phosphatidyl glycerol levels and die of respiratory failure soon after birth. We studied lung biopsy samples of two siblings with a novel homozygous ABCA3 mutation at nucleotide position 578 (c.578C4G), leading to a Pro193Arg amino-acid exchange, who died at 55 and 105 days of age. Light microscopy revealed thickened alveolar septa with abundant myxoid interstitial matrix, marked hyperplasia of type II pneumocytes, desquamation of alveolar macrophages and focal alveolar proteinosis. Surfactant protein-B was detected by immunohistochemistry after antigen retrieval. Transmission electron microscopy showed rare cytoplasmic inclusions with concentric membranes and eccentrically placed electron-dense aggregates. These 'fried-egg'-appearing lamellar bodies differed both from normal lamellar bodies and the larger, poorly formed composite bodies with multiple vesicular inclusions observed in surfactant protein-B deficiency. In conclusion, our findings underscore that the implications of interstitial lung disease in infant lungs differ from those in adults. In infants with a desquamative interstitial pneumonitis pattern, surfactant or ABCA3 mutations should be evaluated. Importantly, these findings support the notion that electron microscopy is useful in distinguishing between surfactant protein-B and ABCA3 deficiency, and has an important role in evaluating biopsies or autopsies of term infants with unexplained severe respiratory failure and interstitial lung disease.

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“…Intratracheal administration of exogenous SP-B to infants with hereditary SP-B deficiency failed to restore lung function, suggesting that SP-B may have functions in addition to promoting formation of a stable surface film in the alveolus (7). Consistent with this hypothesis, SP-B deficiency in mice and human infants was associated with failure to form lamellar bodies and altered pro-SP-C processing (4,8).…”

mentioning

confidence: 85%

Surfactant Protein B (SP-B) −/− Mice Are Rescued by Restoration of SP-B Expression in Alveolar Type II Cells but Not Clara Cells

Lin

Akinbi

et al. 1999

Journal of Biological Chemistry

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Surfactant protein B (SP-B)1 is a critical component of pulmonary surfactant, a lipid-protein mixture which forms a film along the surface of the alveolar epithelium, and is absolutely required for maintenance of alveolar stability at low lung volumes. Surfactant phospholipid mixtures lacking the hydrophobic proteins SP-B and SP-C have poor surface film forming properties, whereas surfactants containing SP-B as the sole protein component rapidly form a stable phospholipid film in vitro and restore lung function in surfactant-deficient preterm animals (1-3). Genetic ablation of the murine SP-B locus leads to acute respiratory distress syndrome at birth resulting in death within minutes (4). Likewise, mutations resulting in SP-B deficiency in human infants lead to severe respiratory distress and death in the neonatal period (5, 6). Intratracheal administration of exogenous SP-B to infants with hereditary SP-B deficiency failed to restore lung function, suggesting that SP-B may have functions in addition to promoting formation of a stable surface film in the alveolus (7). Consistent with this hypothesis, SP-B deficiency in mice and human infants was associated with failure to form lamellar bodies and altered pro-SP-C processing (4, 8).Expression of SP-B is restricted to alveolar Type II cells and nonciliated bronchiolar epithelial (Clara) cells of the pulmonary epithelium (9, 10). In Type II cells, proteolytic processing of the SP-B proprotein is initiated in the multivesicular body with cleavage of an NH 2 -terminal propeptide to generate a processing intermediate of 25 kDa (11,12). Subsequent cleavage of a COOH-terminal propeptide results in liberation of the hydrophobic mature peptide which forms homodimers of 18 kDa. Mature SP-B is stored with surfactant phospholipids in lamellar bodies, the contents of which are released into the alveolar airspace via basal and stimulus-induced secretion (reviewed in (13)).In contrast to the well characterized SP-B biosynthetic pathway in Type II cells, little is known about synthesis and processing of SP-B in Clara cells. Technical problems in the isolation of pure populations of these cells has made study of SP-B processing by Clara cells difficult. Clara cells are the most abundant cell type within the conducting airways of the murine lung, comprising more than 50% of the epithelial cells lining the terminal bronchioles (14,15). Expression of SP-B in cells at the terminal airway/alveolar junction suggests that under certain circumstances, Clara cells may contribute SP-B to the alveolar surfactant pool. In addition to a putative alveolar surfactant function, Clara cell SP-B may also promote formation of a surfactant film in the terminal bronchioles which may be important for maintaining the patency of small conducting airways. Finally, given the widespread distribution of Clara cells in the murine airway, it is possible that SP-B has function(s) that are independent of surfactant activity. In order to better understand the role of SP-B in Type II cells and Clara cells, we ha...

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Ultrastructure of lung in surfactant protein B deficiency.

Cited by 107 publications

References 37 publications

Identification of LBM180, a Lamellar Body Limiting Membrane Protein of Alveolar Type II Cells, as the ABC Transporter Protein ABCA3

Identification of LBM180, a Lamellar Body Limiting Membrane Protein of Alveolar Type II Cells, as the ABC Transporter Protein ABCA3

Ultrastructural and molecular analysis in fatal neonatal interstitial pneumonia caused by a novel ABCA3 mutation

Surfactant Protein B (SP-B) −/− Mice Are Rescued by Restoration of SP-B Expression in Alveolar Type II Cells but Not Clara Cells

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