Pulmonary-specific expression of SP-D corrects pulmonary lipid accumulation in SP-D gene-targeted mice

Targeted disruption of the surfactant protein (SP) D (SP-D) gene caused a m arked pulmonary lipoidosis characterized by increased alveolar lung phospho lipids, demonstrating a previously unexpected role for SP-D in surfactant h omeostasis. In the present study, we tested whether the local production of SP-D in the lung influenced surfactant content in SP-D-deficient [SP-D(-/- )] and SP-D wild-type [SP-D(+/+)] mice. Rat SP-D (rSP-D) was expressed unde r control of the human SP-C promoter, producing rSP-D, SP-D(+/+) transgenic mice. SP-D content in bronchoalveolar lavage fluid was increased 30- to 50 -fold in the rSP-D, SP-D(+/+) mice compared with the SP-D(+/+) parental str ain. Lung morphology, phospholipid content, and surfactant protein mRNAs we re unaltered by the increased concentration of SP-D. Likewise, the producti on of endogenous mouse SP-D mRNA was not perturbed by the SP-D transgene. r SP-D, SP-D(+/+) mice were bred to SP-D(-/-) mice to assess whether lung-sel ective expression of SP-D might correct lipid homeostasis abnormalities in the SP-D( -/-) mice. Selective expression of SP-D in the respiratory epithe lium had no adverse effects on lung function, correcting surfactant phospho lipid content and decreasing phosphatidylcholine incorporation significantl y. SP-D regulates surfactant lipid homeostasis, functioning locally to inhi bit surfactant phospholipid incorporation in the lung parenchyma and mainta ining alveolar phospholipid content in the alveolus. Marked increases in bi ologically active tissue and alveolar SP-D do not alter lung morphology, ma crophage abundance or structure, or surfactant accumulation.