{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T23:55:12Z","timestamp":1791503712796,"version":"4.3.4"},"reference-count":19,"publisher":"American Physiological Society","issue":"3","funder":[{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["NIH R01 HL085453"],"award-info":[{"award-number":["NIH R01 HL085453"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"MEXT | Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["Kakenhi 16K21750"],"award-info":[{"award-number":["Kakenhi 16K21750"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007263","name":"Astellas Foundation for Research on Metabolic Disorders","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007263","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["NIH R01 HL118342"],"award-info":[{"award-number":["NIH R01 HL118342"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["NIH R01 HL136721"],"award-info":[{"award-number":["NIH R01 HL136721"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.physiology.org"],"crossmark-restriction":true},"short-container-title":["American Journal of Physiology-Lung Cellular and Molecular Physiology"],"published-print":{"date-parts":[[2022,3,1]]},"abstract":"<jats:p> Hereditary pulmonary alveolar proteinosis (hPAP) is a rare disorder caused by recessive mutations in GM-CSF receptor subunit \u03b1\/\u03b2 genes ( CSF2RA\/ CSF2RB, respectively) characterized by impaired GM-CSF-dependent surfactant clearance by alveolar macrophages (AMs) resulting in alveolar surfactant accumulation and hypoxemic respiratory failure. Because hPAP is caused by CSF2RA mutations in most patients, we created an animal model of hPAP caused by Csf2ra gene disruption ( Csf2ra<jats:sup>\u2013\/\u2013<\/jats:sup> mice) and evaluated the effects on AMs and lungs. Macrophages from Csf2ra<jats:sup>\u2013\/\u2013<\/jats:sup> mice were unable to bind and clear GM-CSF, did not exhibit GM-CSF signaling, and had functional defects in phagocytosis, cholesterol clearance, and surfactant clearance. Csf2ra<jats:sup>\u2013\/\u2013<\/jats:sup> mice developed a time-dependent, progressive lung disease similar to hPAP in children caused by CSF2RA mutations with respect to the clinical, physiological, histopathological, biochemical abnormalities, biomarkers of PAP lung disease, and clinical course. In contrast, Csf2ra<jats:sup>+\/\u2013<\/jats:sup> mice had functionally normal AMs and no lung disease. Pulmonary macrophage transplantation (PMT) without myeloablation resulted in long-term engraftment, restoration of GM-CSF responsiveness to AMs, and a safe and durable treatment effect that lasted for the duration of the experiment (6 mo). Results demonstrate that homozygous (but not heterozygous) Csf2ra gene ablation caused hPAP identical to hPAP in children with CSF2RA mutations, identified AMs as the cellular site of hPAP pathogenesis in Csf2ra<jats:sup>\u2013\/\u2013<\/jats:sup> mice, and have implications for preclinical studies supporting the translation of PMT as therapy of hPAP in humans. <\/jats:p>","DOI":"10.1152\/ajplung.00175.2021","type":"journal-article","created":{"date-parts":[[2022,1,19]],"date-time":"2022-01-19T13:01:13Z","timestamp":1642597273000},"page":"L438-L448","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":22,"title":["A murine model of hereditary pulmonary alveolar proteinosis caused by homozygous <i>Csf2ra<\/i> gene disruption"],"prefix":"10.1152","volume":"322","author":[{"given":"Kenjiro","family":"Shima","sequence":"first","affiliation":[{"name":"Translational Pulmonary Science Center, Cincinnati Children\u2019s Hospital 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