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 deltaE1-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 alpha-naphthyl acetate esterase (alpha-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.
Division of Pulmonary Biology, Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Z K
ZK
Zsengellér
J A
JA
Reed
C J
CJ
Bachurski
A M
AM
LeVine
S
S
Forry-Schaudies
R
R
Hirsch
J A
JA
Whitsett
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D004195:Disease Models, Animal; D015870:Gene Expression / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000172:deficiency* / Q000235:genetics; D006651:Histocytochemistry; D008168:Lung / Q000473:pathology*; D016676:Macrophages, Alveolar / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D009284:Naphthols / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011510:Proteolipids / Q000378:metabolism; D011649:Pulmonary Alveolar Proteinosis / Q000235:genetics* / Q000628:therapy; D011663:Pulmonary Surfactants / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors / Q000276:immunology
D009284:Naphthols; D018809:Proliferating Cell Nuclear Antigen; D011510:Proteolipids; D011663:Pulmonary Surfactants; D011948:Receptors, Antigen, T-Cell; C027876:alpha-naphthyl acetate; D016178:Granulocyte-Macrophage Colony-Stimulating Factor