Ultrastructure of Lamellar Bodies in Congenital Surfactant Deficiency

Edwards, Vern; Cutz, Ernest; Viero, Sandra; Moore, Aideen M.; Nogee, Lawrence M.

doi:10.1080/01913120500323480

Cited by 74 publications

(44 citation statements)

References 19 publications

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“…In the human lung, ABCA3 expression increased in association with increased surfactant protein expression and type II cell maturation, as indicated by the formation of lamellar bodies (Stahlman et al 1992). Mutations in the human ABCA3 gene cause fatal respiratory distress in the newborn period associated with surfactant dysfunction; surfactant lipid abnormalities; and the formation of small, dense lamellar bodies (Shulenin et al 2004;Edwards et al 2005;Garmany et al 2006). Recent studies demonstrating that inhibition of ABCA3 in type II cells disturbs lamellar body synthesis and lipid transport provide further support for the importance of ABCA3 in surfactant homeostasis (Cheong et al 2006).…”

Section: Discussionmentioning

confidence: 99%

“…Most infants with ABCA3-related lung disease developed respiratory failure in the first hours after birth, generally succumbing from surfactant deficiency and respiratory failure in the first months of life. Electron microscopic evaluation of lung tissue from infants with ABCA3 deficiency demonstrated abnormally small, dense, cytoplasmic inclusions with the absence of normal lamellar bodies and tubular myelin, findings that have been useful for the diagnosis of ABCA3-related disease (Shulenin et al 2004;Edwards et al 2005). Abnormalities in lipid content and function were observed in surfactant from patients with ABCA3-related pulmonary disease (Garmany et al 2006).…”

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confidence: 99%

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Expression of ABCA3 in Developing Lung and Other Tissues

Stahlman

Besnard

Wert

et al. 2006

J Histochem Cytochem.

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ABCA3 is a member of the ATP-binding cassette (ABC) family of transport proteins and is required for perinatal respiratory adaptation. Monoclonal and polyclonal antibodies were generated against a recombinant human ABCA3 peptide and used to assess its expression in the developing lung and adult tissues. Immunostaining for ABCA3 was detected at highest levels in type II epithelial cells of the lung but was also noted in other organs including liver, stomach, kidney, adrenal, pancreas, trachea, and brain. In the fetal lung, ABCA3 staining and mRNA increased prior to birth. Like other surfactant protein genes, ABCA3 expression was induced by thyroid transcription factor-1 in vitro. ABCA3 was coexpressed with SP-B and proSP-C in type II epithelial cells. ABCA3 staining was detected surrounding large, intracellular organelles consistent with its association with lamellar bodies. In the human fetal lung, ABCA3 staining was not detected prior to 22-23 weeks of gestation, except in the presence of pulmonary inflammation. ABCA3 was detected in type II epithelial cells of the human lung from 28 weeks of gestation and thereafter. Postnatally, intense ABCA3 staining was observed in hyperplastic epithelial cells relining injured airways in infants with chronic lung disease. Localization and regulation of ABCA3 in the respiratory epithelium is consistent with its proposed role in surfactant homeostasis. The role of ABCA3 in extrapulmonary tissues and organs remains to be elucidated. This manuscript contains online supplemental material at http://www.jhc.org . Please visit this article online to view these materials.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Expression of ABCA3 in Developing Lung and Other Tissues

Stahlman

Besnard

Wert

et al. 2006

J Histochem Cytochem.

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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: 99%

“…1,14 In contrast to surfactant protein-B deficiency, in ABCA3 mutations, a different, characteristic phenotype of lamellar bodies has been described. 1,14 Cytoplasmic inclusions with tightly packed concentric membranes and distinctive electron dense aggregates of 'fried-egg' appearance are present in congenital surfactant deficiency caused by ABCA3 mutations.…”

Section: Abca3 In Neonatal Pneumoniamentioning

confidence: 99%

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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“…ABCA3 is required for normal lamellar body formation in AT2 cells (17). Similarly, the lamellar bodies in electron micrographs from lung tissue of infants with surfactant deficiency and ABCA3 mutations have dense inclusions and are structurally immature (15,18,19). ABCA3 expressed exogenously in cultured cells, in the absence of surfactant proteins, facilitates the transfer of phosphatidylcholine and cholesterol into the lysosomes, the likely progenitor of lamellar bodies, whereas the surfactant in infants with ABCA3 mutations has decreased phosphatidylcholine content (17,20).…”

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confidence: 99%

ABCA3 Is Critical for Lamellar Body Biogenesis in Vivo

Cheong

Zhang

Madesh

et al. 2007

Journal of Biological Chemistry

137

102

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Mutations in ATP-binding cassette transporter A3 (human ABCA3) protein are associated with fatal respiratory distress syndrome in newborns. We therefore characterized mice with targeted disruption of the ABCA3 gene. Homozygous Abca3 ؊/؊ knock-out mice died soon after birth, whereas most of the wild type, Abca3 ؉/؉ , and heterozygous, Abca3 ؉/؊ , neonates survived. The lungs from E18.5 and E19.5 Abca3 ؊/؊ mice were less mature than wild type. Alveolar type 2 cells from Abca3 ؊/؊ embryos contained no lamellar bodies, and expression of mature SP-B protein was disrupted when compared with the normal lung surfactant system of wild type embryos. Small structural and functional differences in the surfactant system were seen in adult Abca3 ؉/؊ compared with Abca3 ؉/؉ mice. The heterozygotes had fewer lamellar bodies, and the incorporation of radiolabeled substrates into newly synthesized disaturated phosphatidylcholine, phosphatidylglycerol, phosphatidylethanolamine, and phosphatidylserine in both lamellar bodies and surfactant was lower than in Abca3 ؉/؉ mouse lungs. In addition, since the fraction of near term Abca3 ؊/؊ embryos was significantly lower than expected from Mendelian inheritance ABCA3 probably plays roles in development unrelated to surfactant. Collectively, these findings strongly suggest that ABCA3 is necessary for lamellar body biogenesis, surfactant protein-B processing, and lung development late in gestation.Lung surfactant is a complex mixture of 90% lipids, predominantly dipalmitoylphosphatidylcholine, and 10% proteins (SP 2 -A, SP-B, and SP-C) that functions to lower surface tension at the interface between air and the surface lining layer of the alveolar epithelium and prevents lung collapse on end expiration (1-3). The surfactant proteins SP-B and SP-C and lipids are transported to and stored in lamellar bodies, the intracellular secretory organelles of the alveolar epithelial type 2 (AT2) cell through which pulmonary surfactant homeostasis is regulated (4 -6). The final steps in post-translational modification of both SP-B and SP-C occur in lamellar bodies (7-11). One of the striking abnormalities observed in hereditary SP-B deficiency, which is characterized by deficiencies of surfactant quantity and function, is derangement of lamellar body morphology (12), abnormalities that are replicated in the SP-B knock-out mouse (13,14).Fatal deficiencies of lung surfactant in the neonate and interstitial lung disease have recently been associated with mutations in the ATP-binding cassette protein A3 gene (ABCA3) (15,16). ABCA3 is required for normal lamellar body formation in AT2 cells (17). Similarly, the lamellar bodies in electron micrographs from lung tissue of infants with surfactant deficiency and ABCA3 mutations have dense inclusions and are structurally immature (15,18,19). ABCA3 expressed exogenously in cultured cells, in the absence of surfactant proteins, facilitates the transfer of phosphatidylcholine and cholesterol into the lysosomes, the likely progenitor of lamellar bodies, whereas the ...

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Ultrastructure of Lamellar Bodies in Congenital Surfactant Deficiency

Cited by 74 publications

References 19 publications

Expression of ABCA3 in Developing Lung and Other Tissues

Expression of ABCA3 in Developing Lung and Other Tissues

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

ABCA3 Is Critical for Lamellar Body Biogenesis in Vivo

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