Adenovirus-Mediated Granulocyte-Macrophage Colony-Stimulating Factor Improves Lung Pathology of Pulmonary Alveolar Proteinosis in Granulocyte-Macrophage Colony-Stimulating Factor-Deficient Mice

Mutation of the granulocyte-macrophage colony-stimulating factor (GM-CSF) gene by homologous recombination causes progressive pulmonary alveolar proteinosis (PAP) in GM-CSF-deficient mice (GM–/–). The present study tested whether adenovirus-mediated expression of GM-CSF alters the progression of PAP in GM–/– mice. Adult mice were pretreated with an anti-T cell receptor (TCR) antibody to block T cell-mediated immune response, followed by intratracheal instillation of ΔE1–E3 replication-deficient adenovirus expressing mouse GM-CSF (Av1mGM). Mice were killed 1, 3, and 5 weeks after treatment to assess lungs for GM-CSF, surfactant protein B (SP-B), alveolar macrophage maturation, and type II cell proliferation. GM-CSF was detected in BAL fluid from GM–/– mice 1 week after Av1mGM treatment, and GM-CSF mRNA was detected by RT-PCR through 5 weeks. Five weeks after Av1mGM treatment, PAP was improved and SP-B decreased as assessed by ELISA and immunostaining. Increased numbers of alveolar macrophages stained with α-naphthyl acetate esterase (α-NAE) following treatment with Av1mGM. Local expression of GM-CSF with a recombinant adenovirus ameliorated PAP in the GM–/– mice in association with enhanced maturation of alveolar macrophages. Lung pathology in granulocyte-macrophage colony-stimulating factor (GM-CSF)-deficient mice (GM–/–) is similar to that in humans with pulmonary alveolar proteinosis (PAP). The efficacy of somatic cell gene therapy for PAP was tested in GM–/– mice. PAP was improved by adenovirus-mediated gene transfer of mouse GM-CSF cDNA to pulmonary cells.