Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
 6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Secondary pulmonary alveolar proteinosis (PAP) has been described in several clinical settings that can be grouped into three main categories: infections of the lung; haematological malignancies and other conditions that alter the patient's immune status; and exposure to inhaled chemicals and minerals. Recent studies reported that anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibody was present in the serum of patients with idiopathic PAP but not in patients with secondary PAP or in normal subjects. The present report describes the interesting case of a patient with Behcet's disease and PAP. The absence of anti-GM-CSF antibodies in this patient suggested a diagnosis of secondary PAP.
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PMID:Pulmonary alveolar proteinosis in a patient with Behcet's disease. 1921 Jun 51

Pulmonary alveolar proteinosis is a rare disease characterized by the accumulation of lipoproteinaceous material derived from alveolar surfactant in the alveoli, with a consequent deterioration in gas exchange. Pathogenesis is related to impaired phagocytic function of alveolar macrophages. In recent years, a new treatment for pulmonary alveolar proteinosis-consisting of subcutaneous administration of granulocyte-macrophage colony-stimulating factor (GM-CSF)-has become available. The commonly accepted treatment, and the one to have shown greatest efficacy in pulmonary alveolar proteinosis, is whole lung lavage. Instead of subcutaneous administration, GM-CSF can also be inhaled as an aerosol. This route of administration of GM-CSF is safe and effective in the treatment of pulmonary alveolar proteinosis and represents an alternative to subcutaneous administration or whole lung lavage. We present a patient with pulmonary alveolar proteinosis who was treated with inhaled GM-CSF and describe her clinical and functional outcome after 1 year of treatment.
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PMID:[Response to inhaled granulocyte-macrophage colony-stimulating factor in a patient with alveolar proteinosis]. 1928 15

Whole lung lavage (WLL) is currently the standard therapy for pulmonary alveolar proteinosis (PAP). Nevertheless, some PAP patients respond poorly to WLL or require it frequently. The present paper reports a patient with autoimmune PAP with persistent disease despite three WLL treatments over 10 months. Plasmapheresis with ten 1.5-L plasma exchanges was performed, which lowered the serum granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibody level from 250 microg mL(-1) to 156 microg mL(-1) but did not improve respiratory impairment. Further WLL therapy was required and transiently effective. Serum GM-CSF autoantibody levels declined progressively, reaching a value of 56 microg mL(-1) 80 weeks after completion of plasmapheresis. However, this decrease was not accompanied by clinical improvement and the patient required additional WLL therapy. The results confirm that minor reductions in serum granulocyte-macrophage colony-stimulating factor autoantibody levels from plasmapheresis are not reflected in clinical improvement in the severity of lung disease in pulmonary alveolar proteinosis.
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PMID:Plasmapheresis for treatment of pulmonary alveolar proteinosis. 1940 56

Pulmonary alveolar proteinosis (PAP) is a rare disorder characterized by ineffective clearance of surfactant by alveolar macrophages. Through recent studies with genetically altered mice, the etiology of this idiopathic disease is becoming clearer. Functional deficiency of granulocyte-macrophage colony-stimulating factor (GM-CSF) appears to contribute to disease pathogenesis because mutant mice deficient in GM-CSF or its receptor spontaneously develop PAP. Recent human studies further suggest a connection between PAP and defective GM-CSF activity because inactivating anti-GM-CSF autoantibodies are observed in all patients with idiopathic PAP, and additional rare cases of PAP in children have been accompanied by genetic defects in the alpha chain of the GM-CSF receptor. In patients and mouse models of PAP, deficient GM-CSF activity appears to result in defective alveolar macrophages that are unable to maintain pulmonary surfactant homeostasis and display defective phagocytic and antigen-presenting capabilities. The most recent studies also suggest that neutrophil dysfunction additionally contributes to the increased susceptibility to lung infections seen in PAP. Because the phenotypic and immunologic abnormalities of PAP in mouse models can be corrected by GM-CSF reconstituting therapies, early clinical trials are underway utilizing administration of GM-CSF to potentially treat human PAP. The development of novel treatment approaches for PAP represents a dramatic illustration in pulmonary medicine of the "bench-to-bedside" process, in which basic scientists, translational researchers, and clinicians have joined together to rapidly take advantage of the unexpected observations frequently made in the modern molecular biology research laboratory.
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PMID:Pulmonary alveolar proteinosis: a bench-to-bedside story of granulocyte-macrophage colony-stimulating factor dysfunction. 1966 56

We identified 18 patients with the distinct clinical phenotype of susceptibility to disseminated nontuberculous mycobacterial infections, viral infections, especially with human papillomaviruses, and fungal infections, primarily histoplasmosis, and molds. This syndrome typically had its onset in adulthood (age range, 7-60 years; mean, 31.1 years; median, 32 years) and was characterized by profound circulating monocytopenia (mean, 13.3 cells/microL; median, 14.5 cells/microL), B lymphocytopenia (mean, 9.4 cells/microL; median, 4 cells/microL), and NK lymphocytopenia (mean, 16 cells/microL; median, 5.5 cells/microL). T lymphocytes were variably affected. Despite these peripheral cytopenias, all patients had macrophages and plasma cells at sites of inflammation and normal immunoglobulin levels. Ten of these patients developed 1 or more of the following malignancies: 9 myelodysplasia/leukemia, 1 vulvar carcinoma and metastatic melanoma, 1 cervical carcinoma, 1 Bowen disease of the vulva, and 1 multiple Epstein-Barr virus(+) leiomyosarcoma. Five patients developed pulmonary alveolar proteinosis without mutations in the granulocyte-macrophage colony-stimulating factor receptor or anti-granulocyte-macrophage colony-stimulating factor autoantibodies. Among these 18 patients, 5 families had 2 generations affected, suggesting autosomal dominant transmission as well as sporadic cases. This novel clinical syndrome links susceptibility to mycobacterial, viral, and fungal infections with malignancy and can be transmitted in an autosomal dominant pattern.
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PMID:Autosomal dominant and sporadic monocytopenia with susceptibility to mycobacteria, fungi, papillomaviruses, and myelodysplasia. 2004 Jul 66

A 27-year-old man was admitted to our hospital complaining of a persistent high fever since August 2007. Chest radiography showed infiltration shadows in the right lower lung field. Chest CT revealed scattered small nodular shadows and patchy consolidations in the right lower lobe. He was diagnosed as secondary pulmonary alveolar proteinosis (sPAP) associated with myelodysplastic syndrome (MDS), confirmed by video-assisted thoracic surgery (VATS) and bone marrow aspiration. Sera were negative for anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibody. He developed a subcutaneous abscess and meningitis caused by M. absessus after VATS. After a long-course of antibiotic therapy, an allogenic peripheral blood stem cell transplantation was performed. But he died of graft versus host disease and M. abscessus sepsis 87 days after transplantation.
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PMID:[A case of secondary pulmonary alveolar proteinosis associated with myelodysplastic syndrome, complicated with disseminated M. abscessus infection]. 2005 90

Surfactant accumulates in alveolar macrophages of granulocyte-macrophage colony-stimulating factor (GM-CSF) knockout (KO) mice and pulmonary alveolar proteinosis (PAP) patients with a functional loss of GM-CSF resulting from neutralizing anti-GM-CSF antibody. Alveolar macrophages from PAP patients and GM-CSF KO mice are de-ficient in peroxisome proliferator-activated receptor-gamma (PPARgamma) and ATP-binding cassette (ABC) lipid transporter ABCG1. Previous studies have demonstrated that GM-CSF induces PPARgamma. We therefore hypothesized that PPARgamma promotes surfactant catabolism through regulation of ABCG1. To address this hypothesis, macrophage-specific PPARgamma (MacPPARgamma) knockout mice were utilized. MacPPARgamma KO mice develop foamy, lipid-engorged Oil Red O positive alveolar macrophages. Lipid analyses revealed significant increases in the cholesterol and phospholipid contents of MacPPARgamma KO alveolar macrophages and extracellular bronchoalveolar lavage (BAL)-derived fluids. MacPPARgamma KO alveolar macrophages showed decreased expression of ABCG1 and a deficiency in ABCG1-mediated cholesterol efflux to HDL. Lipid metabolism may also be regulated by liver X receptor (LXR)-ABCA1 pathways. Interestingly, ABCA1 and LXRbeta expression were elevated, indicating that this pathway is not sufficient to prevent surfactant accumulation in alveolar macrophages. These results suggest that PPARgamma mediates a critical role in surfactant homeostasis through the regulation of ABCG1.
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PMID:Targeted PPAR{gamma} deficiency in alveolar macrophages disrupts surfactant catabolism. 2006 73

Pulmonary alveolar proteinosis (PAP) is a rare diffuse lung disease characterized by abnormal accumulation of surfactant-associated phospholipoproteinaceous material in the pulmonary alveoli. The clinical findings of slow-onset dyspnea or dyspnea on exertion and persistent dry cough are nonspecific; radiographic findings of "bat-wing configuration" and "crazy paving" appearance in high-resolution computed tomography are suggestive, but not diagnostic of PAP. The current gold standard of PAP diagnosis involves histopathological examination of alveolar specimens obtained from bronchoalveolar lavage and transbronchial lung biopsy. The characteristic histopathological features are intraalveolar periodic acid Schiff (PAS)-positive eosinophilic homogeneous material with well-preserved architecture ofalveolar septa. The current standard medical treatment of PAP involves the physical removal of the surfactant-associated phospholipoproteinaceous alveolar deposit by whole lung lavage, which causes clinical and radiological improvement in a majority of patients. Some patients have been successfully treated with recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF).
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PMID:Pulmonary alveolar proteinosis: an overview for internists and hospital physicians. 2046 23

The aim of the project is to develop a novel method estimating granulocyte-macrophage colony-stimulating factor (GM-CSF) neutralizing capacity with high-throughput and good reproducibility. For that purpose, we designed a cell-free receptor binding assay consisting of a solid-phase recombinant soluble GM-CSF receptor alpha (GMRalpha) and a biotinylated GM-CSF (bGM-CSF). Using this system, competitive inhibition of bGM-CSF binding to soluble GM-CSF receptor alpha (sGMRalpha) by GM-CSF autoantibody or IgG fractions from the sera of patients with pulmonary alveolar proteinosis was examined, resulting in excellent reproducibility. Binding inhibition was correlated with growth inhibition of TF-1 cells, a GM-CSF dependent cell line. These results suggest that our cell-free system can be applied to estimate the neutralizing capacity of GM-CSF autoantibodies ex vivo.
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PMID:A cell-free assay to estimate the neutralizing capacity of granulocyte-macrophage colony-stimulating factor autoantibodies. 2062 Nov 2

Pulmonary alveolar proteinosis (PAP) is a rare disease of the lung characterized by the accumulation of surfactant-derived lipoproteins within pulmonary alveolar macrophages and alveoli, resulting in respiratory insufficiency and increased infections. The disease is caused by a disruption in surfactant catabolism by alveolar macrophages due to loss of functional granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling. The underlying molecular mechanisms causing deficiencies in GM-CSF signaling are as follows: 1) high levels of neutralizing GM-CSF autoantibodies observed in autoimmune PAP; 2) mutations in CSF2RA, the gene encoding the alpha chain of the GM-CSF receptor, observed in hereditary PAP; and 3) reduced numbers and function of alveolar macrophages as a result of other clinical diseases seen in secondary PAP. Recent studies investigating the biology of GM-CSF have revealed that not only does this cytokine have an indispensable role in lung physiology, but it is also a critical regulator of innate immunity and lung host defense.
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PMID:Immune dysregulation in the pathogenesis of pulmonary alveolar proteinosis. 2062 72


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