Analysis of the lung pathology and alveolar macrophage function in the acid sphingomyelinase-deficient mouse model of Niemann-Pick disease

Types A and 8 Niemann-Pick disease (NPD) are lipid storage diseases caused by the deficient activity of the lysosomal enzyme, acid sphingomyelinase (A SM). Type B NPD is associated with progressive pulmonary function decline a nd frequent respiratory infections. ASM knock-out (ASMKO) mice are availabl e as a model for NPD, but the lung pathology in these mice has not been ade quately characterized. This study shows that by in weeks of age ASMKO mice have a significantly higher number of cells in their pulmonary airspaces th an normal mice, consisting primarily of enlarged and often multinucleated m acrophages. These mice also have much higher levels of sphingomyelin in the ir airspaces at 10 weeks of age, and both cell numbers and sphingomyelin co ncentrations remain elevated until 26 weeks of age. In these older mice an increased number of neutrophils is also seen. The alveolar cell population in the ASMKO mice produces less superoxide when stimulated, but this can be corrected by providing recombinant ASM to the culture media. Elevated leve ls of the chemokines macrophage inflammatory protein-2 and macrophage infla mmatory protein-1 alpha were also present in the bronchoalveolar lavage flu id of ASMKO mice, and this correlated with increased production of these ch emokines by cultured macrophages and enhanced immunostaining in situ. Also, lung histology showed increased cellularity in the alveolar walls of ASMKO mice, but no evidence of fibrosis. Ultrastructural analysis of the lungs s howed that the ASMKO mice have similar pathologic features to human NPD pat ients. with variable lipid storage evident in type I pneumocytes, endotheli al cells, acid airway ciliated epithelia. The alveolar macrophage, however, was the most dramatically affected cell type in both mice and humans. Thes e studies indicate that the ASMKO mice can be used as a model to study the lung pathology associated with NPD, and demonstrate that the cellular and b iochemical analysis of pulmonary airspaces may be a useful approach to moni toring disease progression and/or treatment.