title: Modeling pulmonary alveolar microlithiasis by epithelial deletion of the Npt2b sodium phosphate cotransporter reveals putative biomarkers and strategies for treatment.
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.
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, The University of Cincinnati, Cincinnati, OH 45267, USA.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Saito
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, The University of Cincinnati, Cincinnati, OH 45267, USA.
authors.forename: Nikolaos M
authors.initials: NM
authors.lastname: Nikolaidis
authors.affiliation: Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
authors.forename: Hassane
authors.initials: H
authors.lastname: Amlal
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, The University of Cincinnati, Cincinnati, OH 45267, USA.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Uehara
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, The University of Cincinnati, Cincinnati, OH 45267, USA.
authors.forename: Jason C
authors.initials: JC
authors.lastname: Gardner
authors.affiliation: Vontz Core Imaging Laboratory, Vontz Center for Molecular Studies, The University of Cincinnati, Cincinnati, OH 45267, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: LaSance
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, The University of Cincinnati, Cincinnati, OH 45267, USA.
authors.forename: Lori B
authors.initials: LB
authors.lastname: Pitstick
authors.affiliation: Perinatal Institute, Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Bridges
authors.affiliation: Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Wikenheiser-Brokamp
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, The University of Cincinnati, Cincinnati, OH 45267, USA.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: McGraw
authors.affiliation: Pulmonary Imaging Research Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Jason C
authors.initials: JC
authors.lastname: Woods
authors.affiliation: The Sanofi-Genzyme R&D Center, Genzyme, a Sanofi company, Framingham, MA 01701, USA.
authors.forename: Yves
authors.initials: Y
authors.lastname: Sabbagh
authors.affiliation: The Sanofi-Genzyme R&D Center, Genzyme, a Sanofi company, Framingham, MA 01701, USA.
authors.forename: Susan C
authors.initials: SC
authors.lastname: Schiavi
authors.affiliation: Department of Chest Diseases, Faculty of Medicine, Pamukkale University, Denizli 20160, Turkey.
authors.forename: Göksel
authors.initials: G
authors.lastname: Altinişik
authors.affiliation: Department for Respiratory Diseases, University Hospital Centre Zagreb, University of Zagreb School of Medicine, 10000 Zagreb, Croatia.
authors.forename: Marko
authors.initials: M
authors.lastname: Jakopović
authors.affiliation: Department of Diffuse Lung Diseases and Respiratory Failure, Clinical Research Center, National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka 5918555, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Inoue
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, The University of Cincinnati, Cincinnati, OH 45267, USA. frank.mccormack@uc.edu.
authors.forename: Francis X
authors.initials: FX
authors.lastname: McCormack
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood*; D002114:Calcinosis / Q000209:etiology* / Q000503:physiopathology* / Q000628:therapy*; D004032:Diet; D004195:Disease Models, Animal; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D030342:Genetic Diseases, Inborn / Q000209:etiology* / Q000503:physiopathology* / Q000628:therapy*; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008171:Lung Diseases / Q000209:etiology* / Q000503:physiopathology* / Q000628:therapy*; D051379:Mice; D009154:Mutation; D010710:Phosphates / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000378:metabolism; D050614:Sodium-Phosphate Cotransporter Proteins, Type IIb / Q000172:deficiency* / Q000235:genetics*
chemical_list: D015415:Biomarkers; C000610601:Npt2b protein, mouse; D010710:Phosphates; D050614:Sodium-Phosphate Cotransporter Proteins, Type IIb