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Sci Transl Med. 2015 Nov 11;7(313):313ra181. doi: 10.1126/scitranslmed.aac8577.

Modeling pulmonary alveolar microlithiasis by epithelial deletion of the Npt2b sodium phosphate cotransporter reveals putative biomarkers and strategies for treatment.

Author information

1
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, The University of Cincinnati, Cincinnati, OH 45267, USA.
2
Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
3
Vontz Core Imaging Laboratory, Vontz Center for Molecular Studies, The University of Cincinnati, Cincinnati, OH 45267, USA.
4
Perinatal Institute, Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
5
Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
6
Pulmonary Imaging Research Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
7
The Sanofi-Genzyme R&D Center, Genzyme, a Sanofi company, Framingham, MA 01701, USA.
8
Department of Chest Diseases, Faculty of Medicine, Pamukkale University, Denizli 20160, Turkey.
9
Department for Respiratory Diseases, University Hospital Centre Zagreb, University of Zagreb School of Medicine, 10000 Zagreb, Croatia.
10
Department of Diffuse Lung Diseases and Respiratory Failure, Clinical Research Center, National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka 5918555, Japan.
11
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, The University of Cincinnati, Cincinnati, OH 45267, USA. frank.mccormack@uc.edu.

Abstract

Pulmonary alveolar microlithiasis (PAM) is a rare, autosomal recessive lung disorder associated with progressive accumulation of calcium phosphate microliths. Inactivating mutations in SLC34A2, which encodes the NPT2b sodium-dependent phosphate cotransporter, has been proposed as a cause of PAM. We show that epithelial deletion of Npt2b in mice results in a progressive pulmonary process characterized by diffuse alveolar microlith accumulation, radiographic opacification, restrictive physiology, inflammation, fibrosis, and an unexpected alveolar phospholipidosis. Cytokine and surfactant protein elevations in the alveolar lavage and serum of PAM mice and confirmed in serum from PAM patients identify serum MCP-1 (monocyte chemotactic protein 1) and SP-D (surfactant protein D) as potential biomarkers. Microliths introduced by adoptive transfer into the lungs of wild-type mice produce marked macrophage-rich inflammation and elevation of serum MCP-1 that peaks at 1 week and resolves at 1 month, concomitant with clearance of stones. Microliths isolated by bronchoalveolar lavage readily dissolve in EDTA, and therapeutic whole-lung EDTA lavage reduces the burden of stones in the lungs. A low-phosphate diet prevents microlith formation in young animals and reduces lung injury on the basis of reduction in serum SP-D. The burden of pulmonary calcium deposits in established PAM is also diminished within 4 weeks by a low-phosphate diet challenge. These data support a causative role for Npt2b in the pathogenesis of PAM and the use of the PAM mouse model as a preclinical platform for the development of biomarkers and therapeutic strategies.

PMID:
26560359
PMCID:
PMC4764987
DOI:
10.1126/scitranslmed.aac8577
[Indexed for MEDLINE]
Free PMC Article

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