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-C SF) gene by homologous recombination causes progressive pulmonary alve olar proteinosis (PAP) in GM-CSF-deficient mice (GM-/-), The present s tudy tested whether adenovirus-mediated expression of GM-CSF alters th e progression of PAP in GM-/-mice. Adult mice were pretreated with an anti-T cell receptor (TCR) antibody to block T cell-mediated immune re sponse, followed by intratracheal instillation of Delta E1-E3 replicat ion-deficient adenovirus expressing mouse GM-CSF (Av1mGM). Mice were k illed 1, 3, and 5 weeks after treatment to assess lungs for CM-CSF, su rfactant 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 a nd SP-B decreased as assessed by ELISA and immunostaining, Increased n umbers of alveolar macrophages stained with cx-naphthyl acetate estera se (alpha-NAE) following treatment with Av1mGM, Local expression of GM -CSF with a recombinant adenovirus ameliorated PAP in the GM-/- mice i n association with enhanced maturation of alveolar macrophages.