title: Pulmonary epithelial cell expression of GM-CSF corrects the alveolar proteinosis in GM-CSF-deficient mice.
abstract: Mutation of the granulocyte-macrophage colony-stimulating factor (GM-CSF) gene by homologous recombination caused alveolar proteinosis in mice. To further discern the role of GM-CSF in surfactant homeostasis, the synthesis of GM-CSF was directed to the respiratory epithelium of GM-CSF-hull mutant mice (GM-/-) with a chimeric gene expressing GM-CSF under the control of the promoter from the human surfactant protein-C (SP-C) gene. Transgenic mice bearing the SP-C-GM-CSF construct (SP-C-GM+) were bred to GM-/- mice resulting in complete correction of alveolar proteinosis in bitransgenic GM-/-, SP-C-GM+ mice. No effects of the transgene were found outside the lung. GM-CSF was increased in bronchoalveolar lavage fluid of the bitransgenic mice. Surfactant proteins-A and -B and phospholipid in bronchoalveolar lavage fluid were normalized in the GM-/-, SP-C-GM+ mice. SP-A, -B, and -C mRNAs were unaltered in lungs from GM-CSF-deficient and -replete mice. Expression of GM-CSF in respiratory epithelial cells of transgenic mice restores surfactant homeostasis in GM-/- mice. From these findings, we conclude that GM-CSF regulates the clearance or catabolism rather than synthesis of surfactant proteins and lipids.
authors.affiliation: Division of Pulmonary Biology, Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Huffman
authors.forename: W M
authors.initials: WM
authors.lastname: Hull
authors.forename: G
authors.initials: G
authors.lastname: Dranoff
authors.forename: R C
authors.initials: RC
authors.lastname: Mulligan
authors.forename: J A
authors.initials: JA
authors.lastname: Whitsett
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004848:Epithelium / Q000378:metabolism; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use*; D006801:Humans; D008168:Lung / Q000033:anatomy & histology; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D011510:Proteolipids / Q000235:genetics; D011649:Pulmonary Alveolar Proteinosis / Q000235:genetics / Q000628:therapy*; D011663:Pulmonary Surfactants / Q000235:genetics / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D011510:Proteolipids; D011663:Pulmonary Surfactants; D016178:Granulocyte-Macrophage Colony-Stimulating Factor