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1 Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
2 Mount Sinai School of Medicine, New York, New York, USA
* To whom correspondence should be addressed. E-mail: machiko.ikegami{at}chmcc.org.
Types A and B Niemann-Pick disease (NPD) are lipid storage disorders caused by the deficient activity of acid sphingomyelinase (ASM). In humans, NPD is associated with dysfunction of numerous organs including lung. Gene targeting of the ASM gene in transgenic mice produced an animal model with features typical of NDP including pulmonary inflammation. In order to assess mechanisms by which ASM perturbed lung function, lung morphology, surfactant content and metabolism were studied in ASM deficient mice in vivo. Pulmonary inflammation, with increased cellular infiltrates and the accumulation of alveolar material was associated with alterations in surfactant content. Saturated phosphatidylcholine (SatPC) content was increased 2 fold and sphingomyelin content was increased 5.5 fold in lungs of the ASMKO mice. Additional sphingomyelin enhanced the sensitivity of surfactant inhibition by plasma proteins. Clearance of SatPC from the lungs of ASMKO mice was decreased. Catabolism of SatPC by alveolar macrophages from the ASMKO mouse was significantly decreased, likely accounting for decreased pulmonary SatPC in vivo. In summary, ASM is required for normal surfactant catabolism by alveolar macrophages in vivo. Alterations in surfactant composition, including increased sphingomyelin content, contributed to the abnormal surfactant function observed in the ASM deficient mouse.
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