A murine model of hereditary pulmonary alveolar proteinosis caused by homozygous gene disruption.

Hereditary pulmonary alveolar proteinosis (hPAP) is a rare disorder caused by recessive mutations in GM-CSF receptor subunit α/β genes (/, 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 mutations in most patients, we created an animal model of hPAP caused by gene disruption ( mice) and evaluated the effects on AMs and lungs. Macrophages from 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. mice developed a time-dependent, progressive lung disease similar to hPAP in children caused by mutations with respect to the clinical, physiological, histopathological, biochemical abnormalities, biomarkers of PAP lung disease, and clinical course. In contrast, 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) gene ablation caused hPAP identical to hPAP in children with mutations, identified AMs as the cellular site of hPAP pathogenesis in mice, and have implications for preclinical studies supporting the translation of PMT as therapy of hPAP in humans.