Surfactant Composition and Function in Patients with ABCA3 Mutations

Abstract

Mutations in the gene encoding the ATP binding cassette transporter member A3 (ABCA3) are associated with fatal surfactant deficiency. ABCA3 lines the limiting membrane of lamellar bodies within alveolar type-II cells, suggesting a role in surfactant metabolism. The objective of this study was to determine the surfactant phospholipid composition and function in patients with mutations in the ABCA3 gene. Bronchoalveolar lavage (BAL) fluid was analyzed from three groups of infants: 1) Infants with ABCA3 mutations, 2) infants with inherited surfactant protein-B deficiency (SP-B), and 3) patients without parenchymal lung disease (CON). Surfactant phospholipid profile was determined using twodimensional thin-layer chromatography, and surface tension was measured with a pulsating bubble surfactometer. Phosphatidylcholine comprised 41 Ϯ 19% of the total phospholipid in the BAL fluid of the ABCA3 group compared with 78 Ϯ 3% and 68 Ϯ 18%, p ϭ 0.008 and 0.05, of the CON and SP-B groups, respectively. Surface tension was 31.5 Ϯ 9.3 mN/m and was significantly greater than CON but no different from SP-B. We conclude that mutations in ABCA3 are associated with surfactant that is deficient in phosphatidylcholine and has decreased function, suggesting that ABCA3 plays an important role in pulmonary surfactant phospholipid homeostasis. (Pediatr Res 59: [801][802][803][804][805] 2006)

ABCA3 as a Lipid Transporter in Pulmonary Surfactant Biogenesis

“…Especially PC and PG, both of which contain palmitic acid, are abundant in lamellar bodies, accounting for 70% of total PC and 50% of total PG, respectively (10,11), and are crucial in reducing surface tension at the alveolar air-liquid interface. Very recently, the ratio of PC in total surfactant phospholipids extracted from BALF in patients with ABCA3 gene mutation has been reported to be decreased compared with control (35), which is consistent with our data.…”

Deletion of Scap in Alveolar Type II Cells Influences Lung Lipid Homeostasis and Identifies a Compensatory Role for Pulmonary Lipofibroblasts

“…Differences in expression of these mRNAs were not observed in mRNA isolated from total adult lung, indicating the potential for compensatory regulation of gene expression in other lung cell types in the adult. Expression of Abca3, a phospholipid transport protein critical for surfactant production (35,36), was significantly decreased at E18.5, consistent with previous findings demonstrating that SREBP-1c directly induced the Abca3 gene promoter (21). Because the promoter regions of lung surfactant-associated genes (Sftpa, Sftpb, Sftpc, and Sftpd) contain potential DNA-binding sites for SREBPs, we sought to determine whether SREBPs activate the Sftpa, Sftpb, Sftpc, and Sftpd promoters in vitro.…”

“…In Situ Hybridization-In situ hybridization was performed using 35 S-UTP-labeled riboprobe for Scap (a 2175-bp mouse cDNA (GenBank TM accession number GI 47564087), subcloned into pCRII, Invitrogen). In situ hybridizations were performed on lung sections at E12.5, E14.5, E16.5, and E18.5 as described previously (23).…”

Aberrant catalytic cycle and impaired lipid transport into intracellular vesicles in ABCA3 mutants associated with nonfatal pediatric interstitial lung disease

“…Exogenous expression of ABCA3 in cultured cells promotes lipid uptake into intracellular vesicles that generate lamellar body-like vesicles (7,18,21). ABCA3 deficiency in human and mice leads to decreased phosphatidylcholine and phosphatidylglycerol in surfactant, dysgenesis of lamellar bodies, and respiratory distress (1,3,8,11,12,27). Considered together, these results indicate that ABCA3 is an essential lipid transporter in surfactant metabolism.…”