PMID- 26560359 OWN - NLM STAT- MEDLINE DCOM- 20160913 LR - 20181113 IS - 1946-6242 (Electronic) IS - 1946-6234 (Print) IS - 1946-6234 (Linking) VI - 7 IP - 313 DP - 2015 Nov 11 TI - Modeling pulmonary alveolar microlithiasis by epithelial deletion of the Npt2b sodium phosphate cotransporter reveals putative biomarkers and strategies for treatment. PG - 313ra181 LID - 10.1126/scitranslmed.aac8577 [doi] AB - 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. CI - Copyright (c) 2015, American Association for the Advancement of Science. FAU - Saito, Atsushi AU - Saito A AD - Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, The University of Cincinnati, Cincinnati, OH 45267, USA. FAU - Nikolaidis, Nikolaos M AU - Nikolaidis NM AD - Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, The University of Cincinnati, Cincinnati, OH 45267, USA. FAU - Amlal, Hassane AU - Amlal H AD - Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267, USA. FAU - Uehara, Yasuaki AU - Uehara Y AD - Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, The University of Cincinnati, Cincinnati, OH 45267, USA. FAU - Gardner, Jason C AU - Gardner JC AD - Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, The University of Cincinnati, Cincinnati, OH 45267, USA. FAU - LaSance, Kathleen AU - LaSance K AD - Vontz Core Imaging Laboratory, Vontz Center for Molecular Studies, The University of Cincinnati, Cincinnati, OH 45267, USA. FAU - Pitstick, Lori B AU - Pitstick LB AD - Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, The University of Cincinnati, Cincinnati, OH 45267, USA. FAU - Bridges, James P AU - Bridges JP AD - Perinatal Institute, Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. FAU - Wikenheiser-Brokamp, Kathryn A AU - Wikenheiser-Brokamp KA AD - Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. FAU - McGraw, Dennis W AU - McGraw DW AD - Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, The University of Cincinnati, Cincinnati, OH 45267, USA. FAU - Woods, Jason C AU - Woods JC AD - Pulmonary Imaging Research Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. FAU - Sabbagh, Yves AU - Sabbagh Y AD - The Sanofi-Genzyme R&D Center, Genzyme, a Sanofi company, Framingham, MA 01701, USA. FAU - Schiavi, Susan C AU - Schiavi SC AD - The Sanofi-Genzyme R&D Center, Genzyme, a Sanofi company, Framingham, MA 01701, USA. FAU - Altinisik, Goksel AU - Altinisik G AD - Department of Chest Diseases, Faculty of Medicine, Pamukkale University, Denizli 20160, Turkey. FAU - Jakopovic, Marko AU - Jakopovic M AD - Department for Respiratory Diseases, University Hospital Centre Zagreb, University of Zagreb School of Medicine, 10000 Zagreb, Croatia. FAU - Inoue, Yoshikazu AU - Inoue Y AD - Department of Diffuse Lung Diseases and Respiratory Failure, Clinical Research Center, National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka 5918555, Japan. FAU - McCormack, Francis X AU - McCormack FX AD - Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, The University of Cincinnati, Cincinnati, OH 45267, USA. frank.mccormack@uc.edu. LA - eng GR - R01 DK083582/DK/NIDDK NIH HHS/United States GR - DK083582/DK/NIDDK NIH HHS/United States GR - U54 HL127672/HL/NHLBI NIH HHS/United States GR - T32 HL007752/HL/NHLBI NIH HHS/United States GR - R01 HL127455/HL/NHLBI NIH HHS/United States GR - U54HL127672/HL/NHLBI NIH HHS/United States GR - HL127455/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Sci Transl Med JT - Science translational medicine JID - 101505086 RN - 0 (Biomarkers) RN - 0 (Npt2b protein, mouse) RN - 0 (Phosphates) RN - 0 (Sodium-Phosphate Cotransporter Proteins, Type IIb) RN - Pulmonary Alveolar Microlithiasis SB - IM MH - Animals MH - Biomarkers/*blood MH - Calcinosis/*etiology/*physiopathology/*therapy MH - Diet MH - Disease Models, Animal MH - Epithelium/metabolism/pathology MH - Genetic Diseases, Inborn/*etiology/*physiopathology/*therapy MH - Lung/metabolism/pathology MH - Lung Diseases/*etiology/*physiopathology/*therapy MH - Mice MH - Mutation MH - Phosphates/metabolism MH - Pulmonary Alveoli/metabolism MH - Sodium-Phosphate Cotransporter Proteins, Type IIb/*deficiency/*genetics PMC - PMC4764987 MID - NIHMS759956 COIS- Competing interests: Y.S. and S.C.S. are employees of Genzyme, a Sanofi company, and own Sanofi stock. All other authors declare that they have no competing interests. EDAT- 2015/11/13 06:00 MHDA- 2016/09/14 06:00 PMCR- 2016/11/11 CRDT- 2015/11/13 06:00 PHST- 2015/11/13 06:00 [entrez] PHST- 2015/11/13 06:00 [pubmed] PHST- 2016/09/14 06:00 [medline] PHST- 2016/11/11 00:00 [pmc-release] AID - 7/313/313ra181 [pii] AID - 10.1126/scitranslmed.aac8577 [doi] PST - ppublish SO - Sci Transl Med. 2015 Nov 11;7(313):313ra181. doi: 10.1126/scitranslmed.aac8577.