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)

Alveolar macrophages have been implicated in the pathogenesis of a number of acute and chronic lung disorders. A characteristic feature of many of the chronic lung diseases is that the types of macrophages in the lung change, and in most instances, the cells resemble monocyte-like cells. We have previously shown that normal human alveolar macrophages have a decreased capacity to express protein kinase C (PKC)-induced DNA binding activity of the transcription factor activator protein (AP)-1 compared with monocytes. This decrease in AP-1 DNA binding appears to be due to a defect in redox regulation of AP-1 proteins via a decrease in the redox active protein Ref-1. The hypothesis for this study is that there are factors generated during the development of chronic lung disease that increase AP-1 DNA binding activity and Ref-1 production in human alveolar macrophages. We have focused specifically on granulocyte-macrophage colony-stimulating factor (GM-CSF) as a prototype mediator that can be released by alveolar macrophages and is related to the fibrotic process in the lung. We found that after a 24-h incubation with GM-CSF, AP-1 DNA binding was significantly increased in both unstimulated, interleukin (IL)-13, and phorbol myristate acetate (PMA)-stimulated alveolar macrophages and that there was a corresponding increase in Ref-1 protein by Western blot analysis in the PMA-stimulated group. This suggests that disease-related cytokines such as GM-CSF and IL-13 may modulate AP-1 DNA binding activity in alveolar macrophages.
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PMID:GM-CSF increases AP-1 DNA binding and Ref-1 amounts in human alveolar macrophages. 1150 37

Pulmonary alveolar proteinosis (PAP) is characterized by the accumulation of surfactant phospholipids and proteins within the lung alveoli. Important advances have been made over the past 8 years in our understanding of this disease, offering new directions for research and patient care. First, genetically altered mice that are homozygous for a disrupted granulocyte-macrophage colony-stimulating factor (GM-CSF) gene developed a lung lesion with histologic resemblance to PAP. The surfactant is thought to be catabolized or cleared mostly by alveolar macrophages, this process being dependent on GM-CSF. Second, a neutralizing autoantibody against GM-CSF was found in serum and bronchoalveolar lavage fluid of patients with idiopathic PAP but not in healthy controls, thereby raising the suspicion that human PAP may be an autoimmune disease. The relationship between the antibody and disease pathogenesis remains unclear but data suggest that the GM-CSF antibody may have a potential role as a diagnostic test. No specific therapy exists for PAP. Sequential whole lung lavage is the standard of care. Exogenous therapy with GM-CSF may improve the lung disease in some patients with PAP but this therapy is still experimental. Interventions directed at treating a relative GM-CSF deficiency by administration of GM-CSF or lowering the antibody level (i.e. by plasmapheresis or immunosuppression) may hold promise as future therapy for this rare disease.
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PMID:Pulmonary alveolar proteinosis. Clinical manifestations and optimal treatment strategies. 1535 Jan 60

Pulmonary Alveolar Proteinosis (PAP) is characterized by the accumulation of surfactant phospholipids and proteins within the alveoli of lungs. Currently, no specific therapy exists for PAP, and sequential whole lung lavage is standard treatment. Over the past 5 years, important advances have been made in our understanding of alveolar proteinosis, offering new directions for research as well as patient management. First, genetically altered mice that are homozygous for a disrupted granulocyte-macrophage colony-stimulating factor (GM-CSF) gene developed a lung lesion with histologic resemblance to PAP, along with normal hematopoiesis. The biochemical properties of the material filling the airspaces in these mutant mice are similar to those of patients with PAP. Surfactant is thought to be cleared or catabolized mostly by alveolar macrophages, a process dependent on GM-CSF. Second, a neutralizing autoantibody against GM-CSF was found in bronchoalveolar lavage fluid and serum of patients with idiopathic PAP, but not healthy controls. These observations raise the previously unsuspected notion that human alveolar proteinosis may be an autoimmune disease, and suggest that GM-CSF antibody has a potential role as a diagnostic test. The relationship between the antibody and disease pathogenesis remains unknown. Additional data suggest that exogenous therapy with GM-CSF may improve the lung disease in some patients with PAP. Intervention directed at treating a relative GM-CSF deficiency or lowering the antibody (i.e., by plasmapheresis or immunosuppression) may have promise in the therapy of this disease. Alveolar proteinosis may be the first human disease wherein a circulating antibody against a growth factor is linked to disease pathogenesis. Over a relatively short time, studies from ;;knock-out'' mice have been translated to human studies for a new approach to diagnosis and therapy for this disease.
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PMID:Pulmonary Alveolar Proteinosis: recent advances. 1608 4

Granulocyte-macrophage colony-stimulating factor (GM-CSF)-/- mice are an invaluable model for exploring the effects of systemic GM-CSF deficiency. Their lung phenotype exactly reproduces the abnormalities seen in human pulmonary alveolar proteinosis (PAP). However, GM-CSF-/- mice also have significant systemic functional abnormalities. These include immune defects which result in a reduced susceptibility to a range of experimentally induced autoimmune disorders. These immunological defects are also functionally manifest as an impaired ability to resolve a range of infections under certain conditions, usually implicating cellular effectors, including Listeria, Group B streptococcus, adenovirus, Pneumocystis carinii, and malaria. These observations are consistent with the known propensity for patients with PAP to develop a range of opportunistic infections. Conversely, the diminished immunological response to inflammatory stimuli may be beneficial in some settings by limiting inflammatory cell recruitment and pro-inflammatory mediator-release. GM-CSF-/- mice also have distinct fertility defects, manifest as reduced litter size and an increased rate of early fetal loss. These observations may be clinically relevant for women affected by PAP and further support the evaluation of the role of GM-CSF in human reproduction. These observations reinforce the importance of clinicians viewing PAP as a state of systemic functional GM-CSF deficiency, albeit with prominent pulmonary manifestations, rather than purely a 'lung disease'. These systemic manifestations of GM-CSF deficiency should also be considered when deciding on the choice between pulmonary or systemic delivery of GM-CSF as therapy for PAP, as only systemic drug delivery has the potential capacity to correct the systemic manifestations of GM-CSF deficiency in these patients.
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PMID:Extra-pulmonary aspects of acquired pulmonary alveolar proteinosis as predicted by granulocyte-macrophage colony-stimulating factor-deficient mice. 1642 63

Granulocyte-macrophage colony-stimulating factor (GM-CSF) plays an important role in the pathogenesis of acute and chronic lung disease as a major regulator governing the functions of granulocyte and macrophage lineage populations. Chronic obstructive pulmonary disease (COPD) is a disease characterized by lung inflammation with accumulation of neutrophils and increased levels of pro-inflammatory cytokines including GM-CSF in the patient's lungs. We used intranasal administration of lipopolysaccharide (LPS) to mice to induce a disease that resembles COPD with pulmonary inflammation, neutrophil recruitment and release of pro-inflammatory mediators in the bronchoalveolar lavage fluid of the diseased mice. 2 h prior to LPS administration, mice were systemically treated with the murine GM-CSF neutralizing antibody mAb 22E9 per intraperitoneal injection. Intranasal challenge with LPS-induced an increase of total cell number and of neutrophils in the bronchoalveolar lavage fluid. Elevated levels of tumor necrosis factor alpha (TNF-alpha), keratinocyte cytokine and macrophage inflammatory protein-2 (MIP-2) were also observed at this time point. GM-CSF was no longer detectable in bronchoalveolar lavage fluid at 24 h due to its early expression with a peak reached 6 h after LPS challenge. Pretreatment of mice with GM-CSF neutralizing antibody dose-dependently inhibited the accumulation of neutrophils and reduced TNF-alpha and MIP-2 protein levels in bronchoalveolar lavage fluid. These data suggest that neutralization of GM-CSF may represent a novel treatment modality for lung inflammation and in particular for COPD.
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PMID:Lipopolysaccharide-induced lung inflammation is inhibited by neutralization of GM-CSF. 1717 48

Patients with pulmonary alveolar proteinosis (PAP) display impaired surfactant clearance, foamy, lipid-filled alveolar macrophages, and increased cholesterol metabolites within the lung. Neutralizing autoantibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF) are also present, resulting in virtual GM-CSF deficiency. We investigated ABCG1 and ABCA1 expression in alveolar macrophages of PAP patients and GM-CSF knockout (KO) mice, which exhibit PAP-like pulmonary pathology and increased pulmonary cholesterol. Alveolar macrophages from both sources displayed a striking similarity in transporter gene dysregulation, consisting of deficient ABCG1 accompanied by highly increased ABCA1. Peroxisome proliferator-activated receptor gamma (PPARgamma), a known regulator of both transporters, was deficient, as reported previously. In contrast, the liver X receptor alpha, which also upregulates both transporters, was highly increased. GM-CSF treatment increased ABCG1 expression in macrophages in vitro and in PAP patients in vivo. Overexpression of PPARgamma by lentivirus-PPARgamma transduction of primary alveolar macrophages, or activation by rosiglitazone, also increased ABCG1 expression. These results suggest that ABCG1 deficiency in PAP and GM-CSF KO alveolar macrophages is attributable to the absence of a GM-CSF-mediated PPARgamma pathway. These findings document the existence of ABCG1 deficiency in human lung disease and highlight a critical role for ABCG1 in surfactant homeostasis.
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PMID:ABCG1 is deficient in alveolar macrophages of GM-CSF knockout mice and patients with pulmonary alveolar proteinosis. 1784 83

Idiopathic pulmonary alveolar proteinosis (PAP) is a rare lung disorder characterized by excessive accumulation of surfactant lipoprotein in alveoli, which is caused by autoantibody against granulocyte-macrophage colony-stimulating factor. The case of a 42-year-old man with idiopathic PAP, who had worked in steel and cement plants for the past 10 years, is presented. His serum anti-GM-CSF antibody level was markedly increased. Lung specimens obtained during video-assisted thoracoscopic surgery were examined on immunohistochemistry using mAb for localization of surfactant proteins A and D (SP-A and SP-D) and a mucin-like protein, KL-6. Furthermore, western blot analysis of his bronchoalveolar lavage fluid (BALF) was performed using anti-SP-A and anti-SP-D mAb. As well as KL-6, SP-A was localized in the intra-alveolar fine granular substances. But on HE staining the SP-D was localized in SP-A-negative foci corresponding to eosinophilic large globules that were surrounded by an SP-A-positive fine granular structure. On western blot the specificity of mAb was shown. In conclusion, this is the first report demonstrating the striking difference in the distribution of SP-A and SP-D in the intra-alveolar substance of a patient with idiopathic PAP.
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PMID:Differences in the immunolocalization of surfactant protein (SP)-A, SP-D, and KL-6 in pulmonary alveolar proteinosis. 1825 86

The aim of this study was to determine influence of prenatal granulocyte-macrophage colony-stimulating factor (GM-CSF) administration on lung growth, maturation, and vascular endothelial growth factor (VEGF) expression. Twenty Wistar rats received sterile saline (1 mL) or recombinant human GM-CSF (50 micro g/kg) on day 16 of pregnancy. Rats were sacrificed on days 18 and 20 of gestation. H-score for VEGF was calculated immunohistochemically. Alveolar VEGF expression on days 18 and 20 of gestation was significantly higher in the GM-CSF group (P < .01). Increase in VEGF with prenatal GM-CSF administration indicates that GM-CSF may stimulate lung growth and maturation and may be protective against lung disease due to prematurity.
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PMID:Prenatal administration of granulocyte-macrophage colony-stimulating factor increases mesenchymal vascular endothelial growth factor expression and maturation in fetal rat lung. 1900 20

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 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


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