Pulmonary alveolar proteinosis is a disease of decreased availability of GM-CSF rather than an intrinsic cellular defect

Granulocyte-macrophage colony stimulating factor (GM-CSF) deficient mice de velop a pulmonary alveolar proteinosis (PAP) syndrome which is corrected by the administration/expression of GM-CSF. These observations implicate GM-C SF in the pathogenesis of human PAP. We hypothesized that human PAP may inv olve an intrinsic cellular defect in monocytes/macrophages with an inabilit y to produce GM-CSF and/or respond to GM-CSF, Thus, we investigated the cyt okine responses to GM-CSF and LPS from peripheral blood monocytes and alveo lar macrophages from patients with idiopathic PAP and healthy controls. Mac rophage inflammatory protein-1-alpha (MIP) was measured from GM-CSF-stimula ted cells and GM-CSF was measured from LPS-stimulated cells by ELISA. The M IP and GM-CSF production by monocytes and alveolar macrophages did not diff er between PAP patients and healthy controls. Growth of the GM-CSF-dependen t human myeloid cell line TF-1 was inhibited by serum from all patients stu died (n = 10) and all patients had anti-GM-CSF antibody in their serum. The BAL from PAP patients had less detectable GM-CSF by ELISA than healthy con trols (P = 0.05); in contrast, the inhibitory cytokine, interleukin-10 (IL- 10), was increased in PAP compared to controls (P = 0.04). IL-10 is a poten t inhibitor of LPS-stimulated GM-CSF production from healthy control alveol ar macrophages. These studies are the first to demonstrate that circulating monocytes and alveolar macrophages from PAP patients are able to synthesiz e GM-CSF and respond to GM-CSF, suggesting no intrinsic abnormalities in GM CSF signaling. in addition, these observations suggest that PAP in a subset of patients is the result of decreased availability of GM-CSF due to GM-CS F blocking activity and reduced GM-CSF production by IL-10.(C) 2000 Academi c Press.