Aerosolized GM-CSF ameliorates pulmonary alveolar proteinosis in GM-CSF-deficient mice

Surfactant proteins and phospholipids accumulate in the alveolar spaces and lung tissues of mice deficient in granulocyte-macrophage colony-stimulatin g factor (GM-CSF), with pathological findings resembling the histology seen in the human disease pulmonary alveolar proteinosis (PAP). Previous metabo lic studies in GM-CSF-deficient [GM(-/-)] mice indicated that defects in su rfactant clearance cause the surfactant accumulation in PAP. In the present study, GM(-/-) mice were treated daily or weekly with recombinant mouse GM -CSF by aerosol inhalation or intraperitoneal injection for 4-5 wk. Lung hi stology, alveolar macrophage differentiation, and surfactant protein B immu nostaining returned toward normal levels in the GM-CSF aerosol-treated mice . Alveolar and lung tissue saturated phosphatidylcholine and surfactant pro tein B concentrations were significantly decreased after treatment with aer osolized GM-CSF. Cessation of aerosolized GM-CSF for 5 wk resulted in incre ased saturated phosphatidylcholine pool sizes that returned to pretreatment levels. In contrast, PAP did not improve in GM(-/-) mice treated daily for 5 wk with larger doses of systemic GM-CSF. Aerosolized GM-CSF improved PAP in the GM(-/-) mice, demonstrating that surfactant homeostasis can be infl uenced by local administration of GM-CSF to the respiratory tract.