GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR AND PULMONARY SURFACTANT HOMEOSTASIS

Pulmonary surfactant lining the alveolus of the lung is critical to po stnatal adaptation to air breathing. Precise concentrations of surfact ant proteins and lipids are maintained in the alveolar space by a care ful balance among synthesis, recycling, and catabolism. Pulmonary alve olar proteinosis is a rare pulmonary disease associated with accumulat ion of surfactant lipids and proteins in the alveolar spaces. Recent w ork with transgenic mice demonstrated that disruption of the productio n of granulocyte-macrophage colony-stimulating factor (GMCSF) or the c ommon beta-subunit of the GM-CSF receptor caused alveolar proteinosis that was histologically similar to that seen in human patients. The de fect in surfactant homeostasis is caused by decreased surfactant clear ance, mediated (at least in part) by dysfunction of the alveolar macro phage. Local production of GM-CSF corrects the alveolar proteinosis in the GM-CSF knockout mouse. Likewise, transplantation of wild-type bon e 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-CS F 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 fo r the diagnosis and treatment of pulmonary alveolar proteinosis syndro mes in humans.