Alveolar lipoproteinosis in an acid sphingomyelinase-deficient mouse model of Niemann-Pick disease

Machiko Ikegami, Rajwinder Dhami, Edward H. Schuchman

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

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 the dysfunction of numerous organs including the lung. Gene targeting of the ASM gene in transgenic mice produced an animal model with features typical of NPD, including pulmonary inflammation. To assess mechanisms by which ASM perturbed lung function, we studied lung morphology, surfactant content, and metabolism 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 twofold, and sphingomyelin content was increased 5.5-fold in lungs of the ASM knockout (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.

Original languageEnglish
Pages (from-to)L518-L525
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume284
Issue number3 28-3
DOIs
StatePublished - 1 Mar 2003

Keywords

  • Alveolar macrophage
  • Saturated phosphatidylcholine
  • Surface activity
  • Surfactant catabolism
  • Surfactant proteins

Fingerprint

Dive into the research topics of 'Alveolar lipoproteinosis in an acid sphingomyelinase-deficient mouse model of Niemann-Pick disease'. Together they form a unique fingerprint.

Cite this