Pulmonary epithelial cell expression of GM-CSF corrects the alveolar proteinosis in GM-CSF-deficient mice

J Clin Invest. 1996 Feb 1;97(3):649-55. doi: 10.1172/JCI118461.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Disease Models, Animal
  • Epithelium / metabolism
  • Gene Expression
  • Genetic Therapy / methods*
  • Granulocyte-Macrophage Colony-Stimulating Factor / biosynthesis
  • Granulocyte-Macrophage Colony-Stimulating Factor / genetics
  • Granulocyte-Macrophage Colony-Stimulating Factor / therapeutic use*
  • Humans
  • Lung / anatomy & histology
  • Mice
  • Mice, Mutant Strains
  • Mice, Transgenic
  • Promoter Regions, Genetic
  • Proteolipids / genetics
  • Pulmonary Alveolar Proteinosis / genetics
  • Pulmonary Alveolar Proteinosis / therapy*
  • Pulmonary Surfactants / genetics
  • Pulmonary Surfactants / metabolism
  • Tissue Distribution


  • Proteolipids
  • Pulmonary Surfactants
  • Granulocyte-Macrophage Colony-Stimulating Factor