Am. J. Respir. Cell Mol. Biol., Volume 26, Number 1, January, 2002 85-90

Overexpression of Surfactant Protein-C Mature Peptide Causes Neonatal Lethality in Transgenic Mice

Juliana Johnson Conkright, Cheng-Lun Na, and Timothy E. Weaver

Division of Pulmonary Biology, Children's Hospital Medical Center, Cincinnati, Ohio

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_24-57HA) 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_24-57HA 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_24-57HA 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_24-57HA in type II cells resulted in aggregation of SP-C in the early secretory pathway, leading to cytotoxicity and, ultimately, altered lung development.

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