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1 Pulmonary/Critical Care Medicine, Denver Health Medical Center and University of Colorado Health Sciences Center, Denver, Colorado 80262; 5 Division of Pulmonary Biology, Children's Hospital Medical Center, and 4 Pulmonary and Critical Care Medicine, University of Cincinnati School of Medicine, Cincinnati, Ohio 45229-3039; 2 Institute of Chemical Toxicology, Wayne State University, and 3 Department of Pathology, John D. Dingell Veterans Affairs Medical Center, Detroit, Michigan 48201
Targeted
disruption of the surfactant protein (SP) D (SP-D)
gene caused a marked pulmonary lipoidosis characterized by
increased alveolar lung phospholipids, demonstrating a previously
unexpected role for SP-D in surfactant homeostasis. 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 under
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 strain. Lung morphology, phospholipid content, and
surfactant protein mRNAs were unaltered by the increased concentration of SP-D. Likewise, the production of endogenous mouse SP-D mRNA was not
perturbed by the SP-D transgene. rSP-D, SP-D(+/+) mice were
bred to SP-D(
/
) mice to assess whether lung-selective
expression of SP-D might correct lipid homeostasis abnormalities in the
SP-D(
/
) mice. Selective expression of SP-D in the
respiratory epithelium had no adverse effects on lung function,
correcting surfactant phospholipid content and decreasing
phosphatidylcholine incorporation significantly. SP-D regulates
surfactant lipid homeostasis, functioning locally to inhibit surfactant
phospholipid incorporation in the lung parenchyma and maintaining
alveolar phospholipid content in the alveolus. Marked increases in
biologically active tissue and alveolar SP-D do not alter lung
morphology, macrophage abundance or structure, or surfactant accumulation.
pulmonary surfactant; alveolar epithelium; alveolar macrophage; surfactant protein D; surfactant protein A; saturated phosphatidylcholine
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