Modeling pulmonary alveolar microlithiasis by epithelial deletion of the Npt2b sodium phosphate cotransporter reveals putative biomarkers and strategies for treatment
| العنوان: | Modeling pulmonary alveolar microlithiasis by epithelial deletion of the Npt2b sodium phosphate cotransporter reveals putative biomarkers and strategies for treatment |
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| المؤلفون: | Dennis W. McGraw, Yoshikazu Inoue, Yves Sabbagh, Jason D. Gardner, Kathryn A. Wikenheiser-Brokamp, Marko Jakopović, Francis X. McCormack, Atsushi Saito, Yasuaki Uehara, Lori B. Pitstick, Susan C. Schiavi, Kathleen LaSance, Nikolaos M. Nikolaidis, Jason C. Woods, Goksel Altinisik, James P. Bridges, Hassane Amlal |
| المصدر: | Science Translational Medicine. 7 |
| بيانات النشر: | American Association for the Advancement of Science (AAAS), 2015. |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | Lung Diseases, lung disease, Pathology, lung alveolus macrophage, animal cell, Epithelium, lung lavage, Mice, Fibrosis, calcinosis, cytokine, animal, genetics, Lung, pathophysiology, medicine.diagnostic_test, deficiency, General Medicine, respiratory system, biological marker, sodium phosphate cotransporter 2b, lung alveolus, medicine.anatomical_structure, priority journal, monocyte chemotactic protein 1, medicine.medical_specialty, surfactant protein D, animal experiment, Lung injury, Biology, Npt2b protein, mouse, Sodium-Phosphate Cotransporter Proteins, Type IIb, Article, animal tissue, Phosphates, blood, pulmonary alveolar microlithiasis, medicine, Animals, controlled study, human, mouse, phosphate, Lung alveolus, Phospholipidosis, calcium, nonhuman, autosomal recessive disorder, animal model, disease model, Genetic Diseases, Inborn, Surfactant protein D, medicine.disease, Diet, Pulmonary Alveoli, Disease Models, Animal, Bronchoalveolar lavage, protein analysis, Pulmonary alveolar microlithiasis, protein blood level, Mutation, pathology, lung calcification, metabolism, Biomarkers |
| الوصف: | 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, radio-graphic 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 macrophagerich 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. |
| تدمد: | 1946-6242 1946-6234 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::da1c723daf6c246ecf9ec63ecbfe00f9Test https://doi.org/10.1126/scitranslmed.aac8577Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....da1c723daf6c246ecf9ec63ecbfe00f9 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19466242 19466234 |
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