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Division of Pulmonary Biology, Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039
Both surfactant protein (SP) D and
granulocyte-macrophage colony-stimulating factor (GM-CSF) influence
pulmonary surfactant homeostasis, with the deficiency of either protein
causing marked accumulation of surfactant phospholipids in lung tissues
and in the alveoli. To assess whether the effects of each gene were
mediated by distinct or shared mechanisms, surfactant homeostasis and
lung morphology were assessed in 1) double-transgenic mice
in which both SP-D and GM-CSF genes were ablated
[SP-D(
/
),GM(
/
)] and 2) transgenic mice deficient
in both SP-D and GM-CSF in which the expression of GM-CSF was increased
in the lung. Saturated phosphatidylcholine (Sat PC) pool sizes were
markedly increased in SP-D(
/
),GM(
/
) mice, with the effects of
each gene deletion on surfactant Sat PC pool sizes being approximately
additive. Expression of GM-CSF in lungs of SP-D(
/
),GM(
/
) mice
corrected GM-CSF-dependent abnormalities in surfactant catabolism but
did not correct lung pathology characteristic of SP-D deletion. In contrast to findings in GM(
/
) mice, degradation of
[3H]dipalmitoylphosphatidylcholine by alveolar
macrophages from the SP-D(
/
) mice was normal. The emphysema and
foamy macrophage infiltrates characteristic of SP-D(
/
) mice were
similar in the presence or absence of GM-CSF. Taken together, these
findings demonstrate the distinct roles of SP-D and GM-CSF in the
regulation of surfactant homeostasis and lung structure.
phosphatidylcholine; surfactant protein A; pulmonary alveolar proteinosis; emphysema; surfactant protein D; granulocyte-macrophage colony-stimulating factor
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