title: Alveolar lipoproteinosis in an acid sphingomyelinase-deficient mouse model of Niemann-Pick disease.
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.
authors.affiliation: Cincinnati Children's Hospital Medical Center, Division of Pulmonary Biology, Cincinnati, Ohio 45229, USA. machiko.ikegami@cchmc.org
authors.forename: Machiko
authors.initials: M
authors.lastname: Ikegami
authors.forename: Rajwinder
authors.initials: R
authors.lastname: Dhami
authors.forename: Edward H
authors.initials: EH
authors.lastname: Schuchman
mesh_terms: D000818:Animals; D002452:Cell Count; D004195:Disease Models, Animal; D008065:Lipoid Proteinosis of Urbach and Wiethe / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D016676:Macrophages, Alveolar / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009542:Niemann-Pick Diseases / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D010713:Phosphatidylcholines / Q000737:chemistry / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000201:enzymology* / Q000473:pathology; D011663:Pulmonary Surfactants / Q000737:chemistry / Q000378:metabolism; D013108:Sphingomyelin Phosphodiesterase / Q000737:chemistry / Q000172:deficiency* / Q000378:metabolism; D013109:Sphingomyelins / Q000737:chemistry / Q000378:metabolism
chemical_list: D010713:Phosphatidylcholines; D011663:Pulmonary Surfactants; D013109:Sphingomyelins; D013108:Sphingomyelin Phosphodiesterase