title: Overexpression of surfactant protein-C mature peptide causes neonatal lethality in transgenic mice.
abstract: Surfactant replacement preparations containing either surfactant protein (SP)-B or SP-C significantly improve lung function in surfactant-deficient infants, suggesting that these peptides may be functionally redundant. SP-B is absent and SP-C is greatly diminished in the airspaces of SP-B (-/-) mice, which die of respiratory distress syndrome (RDS) shortly after birth. The goal of this study was to determine if elevated expression of SP-C mature peptide could reverse the neonatal lethality in SP-B (-/-) mice. SP-C peptide (residues 24-57 of mouse SP-C proprotein) with a hemagglutinin epitope (SP-C(24-57)HA) was expressed in type II cells of transgenic mice, with the goal of crossing these animals into the SP-B (-/-) background. Unexpectedly, expression of the SP-C(24-57)HA transgene resulted in delayed/arrested lung development and lethal, neonatal RDS of all transgenic progeny in two independent transgenic lines. In transgenic mice, SP-C(24-57)HA was localized predominantly to the endoplasmic reticulum and Golgi; in contrast, SP-B and SP-C were very difficult to detect in the endoplasmic reticulum of wild-type mice. These results suggest that elevated expression of SP-C(24-57)HA in type II cells resulted in aggregation of SP-C in the early secretory pathway, leading to cytotoxicity and, ultimately, altered lung development.
authors.affiliation: Division of Pulmonary Biology, Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, USA.
authors.forename: Juliana Johnson
authors.initials: JJ
authors.lastname: Conkright
authors.forename: Cheng-Lun
authors.initials: CL
authors.lastname: Na
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Weaver
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003433:Crosses, Genetic; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000939:Epitopes; D006056:Golgi Apparatus / Q000378:metabolism; D007150:Immunohistochemistry; D008168:Lung / Q000196:embryology* / Q000254:growth & development; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D010455:Peptides / Q000737:chemistry*; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011487:Protein Conformation; D011510:Proteolipids / Q000096:biosynthesis* / Q000378:metabolism; D011663:Pulmonary Surfactants / Q000096:biosynthesis* / Q000378:metabolism
chemical_list: D000939:Epitopes; D010455:Peptides; D011510:Proteolipids; D011663:Pulmonary Surfactants