title: Pulmonary alveolar proteinosis is a disease of decreased availability of GM-CSF rather than an intrinsic cellular defect.
abstract: Granulocyte-macrophage colony stimulating factor (GM-CSF) deficient mice develop a pulmonary alveolar proteinosis (PAP) syndrome which is corrected by the administration/expression of GM-CSF. These observations implicate GM-CSF in the pathogenesis of human PAP. We hypothesized that human PAP may involve an intrinsic cellular defect in monocytes/macrophages with an inability to produce GM-CSF and/or respond to GM-CSF. Thus, we investigated the cytokine responses to GM-CSF and LPS from peripheral blood monocytes and alveolar macrophages from patients with idiopathic PAP and healthy controls. Macrophage inflammatory protein-1-alpha (MIP) was measured from GM-CSF-stimulated cells and GM-CSF was measured from LPS-stimulated cells by ELISA. The MIP and GM-CSF production by monocytes and alveolar macrophages did not differ between PAP patients and healthy controls. Growth of the GM-CSF-dependent human myeloid cell line TF-1 was inhibited by serum from all patients studied (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 controls (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 potent inhibitor of LPS-stimulated GM-CSF production from healthy control alveolar macrophages. These studies are the first to demonstrate that circulating monocytes and alveolar macrophages from PAP patients are able to synthesize 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-CSF blocking activity and reduced GM-CSF production by IL-10.
authors.affiliation: Department of Pulmonary and Critical Care Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio 44195-5038, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Thomassen
authors.forename: T
authors.initials: T
authors.lastname: Yi
authors.forename: B
authors.initials: B
authors.lastname: Raychaudhuri
authors.forename: A
authors.initials: A
authors.lastname: Malur
authors.forename: M S
authors.initials: MS
authors.lastname: Kavuru
mesh_terms: D000328:Adult; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D006801:Humans; D008168:Lung / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D011649:Pulmonary Alveolar Proteinosis / Q000473:pathology*
chemical_list: D016178:Granulocyte-Macrophage Colony-Stimulating Factor