Abstract
Surfactant protein B (SP-B) mRNA and protein are restricted to alveolar Type II and Clara cells in the respiratory epithelium. In order to investigate the function of SP-B in these distinct cell types, transgenic mice were generated in which SP-B expression was selectively restored in Type II cells or Clara cells of SP-B -/- mice. The 4.8-kilobase murine SP-C promoter was used to generate 3 transgenic lines which expressed human SP-B in Type II cells (mSP-C/hSP-B). Likewise, the 2.3-kilobase murine CCSP promoter was used to generate two transgenic lines which expressed human SP-B in Clara cells (mCCSP/hSP-B). mSP-C/hSP-B and mCCSP/hSP-B transgenic mice were subsequently bred to SP-B +/- mice in order to selectively express SP-B in Type II cells or Clara cells of SP-B -/- mice. Selective restoration of SP-B expression in Type II cells completely rescued the neonatal lethal phenotype in SP-B -/- mice. Expression of SP-B in some, but not all Type II cells of SP-B -/- mice, allowed postnatal survival, but resulted in significantly altered lung architecture and function. Selective restoration of SP-B expression in Clara cells of SP-B -/- mice resulted in respiratory dysfunction and invariable neonatal death, related to the complete absence of mature SP-B peptide in these mice. These results indicate that expression and processing of the SP-B proprotein to the mature peptide in Type II cells is absolutely required for lung function in vivo and that SP-B expression in Clara cells cannot substitute for this function.
Highlights
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
To define the functions of SP-B in each cell type, transgenic mice were generated in which the full-length human SP-B cDNA was targeted to the bronchiolar cells and nonciliated bronchiolar epithelial (Clara) cell or the alveolar Type II cell using either the murine CCSP or the murine SP-C promoter
To target SP-B mRNA to either Type II cells or Clara cells in SP-B Ϫ/Ϫ mice, the mCCSP/ hSP-B and mSP-C/hSP-B transgenic mice were crossed with murine SP-B ϩ/Ϫ hemizygous mice
Summary
Surfactant protein B (SP-B) 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. 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]. In addition to a putative alveolar surfactant function, Clara cell SP-B may promote formation of a surfactant film in the terminal bronchioles which may be important for maintaining the patency of small conducting airways. In order to better understand the role of SP-B in Type II cells and Clara cells, we have generated transgenic mouse lines in which SP-B expression was ablated and restored in a cell-specific manner
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