Granulocyte-macrophage colony-stimulating factor and pulmonary surfactant homeostasis.
Pulmonary surfactant lining the alveolus of the lung is critical to postnatal adaptation to air breathing. Precise concentrations of surfactant proteins and lipids are maintained in the alveolar space by a careful balance among synthesis, recycling, and catabolism. Pulmonary alveolar proteinosis is a rare pulmonary disease associated with accumulation of surfactant lipids and proteins in the alveolar spaces. Recent work with transgenic mice demonstrated that disruption of the production of granulocyte-macrophage colony-stimulating factor (GM-CSF) or the common beta-subunit of the GM-CSF receptor caused alveolar proteinosis that was histologically similar to that seen in human patients. The defect in surfactant homeostasis is caused by decreased surfactant clearance, mediated (at least in part) by dysfunction of the alveolar macrophage. Local production of GM-CSF corrects the alveolar proteinosis in the GM-CSF knockout mouse. Likewise, transplantation of wild-type bone marrow cells expressing the common beta-chain of the GM-CSF receptor restores surfactant homeostasis in the GM-CSF receptor knockout mouse. These studies demonstrate the previously unanticipated role of GM-CSF signaling in surfactant homeostasis, mediated (at least in part) by its actions on the clearance of surfactant lipids and proteins by the alveolar macrophage. These findings may have important implications for the diagnosis and treatment of pulmonary alveolar proteinosis syndromes in humans.
Reed
J A
JA
Division of Pulmonary Biology, Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Whitsett
J A
JA
D000818:Animals; D004195:Disease Models, Animal; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000502:physiology*; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D051379:Mice; D011649:Pulmonary Alveolar Proteinosis / Q000378:metabolism*; D011663:Pulmonary Surfactants / Q000502:physiology*
D011663:Pulmonary Surfactants; D016178:Granulocyte-Macrophage Colony-Stimulating Factor