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)

Recently, granulocyte-macrophage colony-stimulating factor (GM-CSF) auto-antibodies have been found in many patients with pulmonary alveolar proteinosis (PAP). The present study reports a retrospective case series of patients who used aerosolised GM-CSF in the treatment of idiopathic PAP. Between 1999 and 2003, 12 patients elected to receive aerosolised GM-CSF (250 microg b.i.d. every other week) in lieu of whole-lung lavage or observation. Patient characteristics, pulmonary function tests, arterial blood gas analysis, laboratory values and chest radiographs were extracted from the patient's medical records. Of the six patients tested, all had GM-CSF neutralising antibodies. Additionally, abnormalities in GM-CSF gene expression (one patient), receptor expression (two patients) and ability to upregulate adhesion molecules (one patient) were found. All patients except one had a positive response (mean improvements in arterial oxygen tension, alveolar-arterial oxygen gradient, carbon monoxide diffusing capacity of the lung and forced vital capacity were 17.1 mmHg, 18.4 mmHg, 16.6% pred and 13.5% pred, respectively). Two patients made a complete recovery and were disease free 1 and 2 yrs after discontinuing treatment. Four patients showed complete response to both the initial course or when treated again for recurrence after discontinuation of treatment. One patient required dose escalation (500 microg b.i.d.) with complete response. GM-CSF was well tolerated without late toxicity after median (range) follow-up of 30.5 (3-68) months. In conclusion, aerosolised granulocyte-macrophage colony-stimulating factor is safe and effective in treating pulmonary alveolar proteinosis providing an alternative to whole-lung lavage or subcutaneous granulocyte-macrophage colony-stimulating factor.
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PMID:Aerosol granulocyte-macrophage colony-stimulating factor for pulmonary alveolar proteinosis. 1650 60

Pulmonary alveolar proteinosis is a rare syndrome characterized by intra-alveolar accumulation of surfactant components and cellular debris, with minimal interstitial inflammation or fibrosis. The condition has a variable clinical course, from spontaneous resolution to respiratory failure and death due to disease progression or superimposed infections. The standard of care for alveolor proteinosis therapy is represented by whole lung lavage. Important discoveries have been made in the last decade with respect to disease pathogenesis and therapy of both congenital and acquired forms of the disease. Granulocyte-macrophage colony-stimulating factor (GM-CSF) pathway has been shown to be involved in the disease pathogenesis of both acquired and congenital disease. Furthermore, anti-GM-CSF blocking autoantibodies have been found in the serum and bronchoalveolar lavage fluid and seem to interfere with the surfactant clearance by alveolar macrophages in many acquired cases. In the congenital form, the most common defects identified to date are several mutations of the genes encoding GM-CSF receptor subunits or surfactant proteins. Using GM-CSF as a therapeutic tool has also been shown to be effective in at least half of the acquired cases treated, while the importance of quantitative determination of anti-GM-CSF antibodies before and during the course of the therapy, as well as the autoantibody titer-GM-CSF dose relationship are to be elucidated. The congenital form of the disease does not respond to therapy with GM-CSF, consistent with the known primary defects and differences in disease pathogenesis.
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PMID:Pulmonary alveolar proteinosis. 1691 9

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

Pulmonary alveolar proteinosis (PAP) is a group of rare diseases with disturbed homeostasis of alveolar surfactant. While 90% of the primary adult forms are caused by granulocyte-macrophage colony-stimulating factor autoantibodies, the underlying cause of the juvenile form remains unknown. In order to distinguish primary from secondary effects in the pathogenesis of these two forms, the present authors studied the surfactant protein processing proteases napsin A and cathepsin H. In total, 16 controls, 20 patients with juvenile PAP and 13 adults with idiopathic PAP were enrolled. Amounts and activities of the proteases in the bronchoalveolar lavage fluid (BALF) were determined by immunoblotting and specific substrate cleavage. Both proteases were present and active in BALF from controls and increased in juvenile and adult PAP patients. The amount of active cathepsin H in relation to total cathepsin H was increased in PAP patients compared with controls. Cystatin C, the physiological inhibitor of cathepsin H in the alveolar space, was not increased to the same degree as cathepsin H, resulting in an imbalance of inhibitor to protease in the alveolar space. A general defect in napsin A or cathepsin H expression or activity was not the specific cause for abnormal surfactant accumulation in juvenile pulmonary alveolar proteinosis.
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PMID:Cathepsin H and napsin A are active in the alveoli and increased in alveolar proteinosis. 1821 60

Antibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF) can be induced when GM-CSF is used as an adjuvant to solid tumor vaccination. Neutralizing anti-GM-CSF IgG has been associated with pulmonary alveolar proteinosis (PAP), and secondary PAP has been linked to myeloid leukemia. We studied 69 patients with acute myeloid leukemia, chronic myeloid leukemia and myelodysplastic syndrome, including 19 patients who received GM-CSF with peptide antigen and incomplete Freund's adjuvant in a vaccine trial for the presence or induction of anti-GM-CSF antibodies. Anti-GM-CSF IgG were present in 36 (52%) patients with myeloid leukemia compared to only 1 of 33 (3%) healthy subjects (P=0.008) and in none of 6 patients with lymphoid leukemia (P=0.0001). Antibody titers were unaffected by vaccination. Anti-GM-CSF IgA and IgM were found in 33 and 20% of patients, respectively; IgA from two patients neutralized GM-CSF. Strikingly, while anti-GM-CSF IgG titers were higher in patients with active disease (n=52) versus those in complete remission (n=14, P=0.0009), GM-CSF expression was not increased in either group. These data are first to show that anti-GM-CSF antibodies of multiple isotypes are present in patients with active myeloid leukemia without PAP and may be useful markers of disease activity.
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PMID:High titer autoantibodies to GM-CSF in patients with AML, CML and MDS are associated with active disease. 1821 69

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

Pulmonary alveolar proteinosis (PAP) due to deficiency of the common beta-chain (beta(c)) of the interleukin-3 (IL-3)/IL-5/granulocyte-macrophage colony-stimulating factor (GM-CSF) receptors is a rare monogeneic disease characterized by functional insufficiency of pulmonary macrophages. Hematopoietic stem cell gene therapy for restoring expression of beta(c)-protein in the hematopoietic system may offer a curative approach. Toward this end, we generated a retroviral construct expressing the murine beta(c) (mbeta(c)) gene and conducted investigations in a murine model of beta(c)-deficient PAP. Functional correction of mbeta(c) activity in mbeta(c)(-/-) bone marrow (BM) cells was demonstrated by restoration of in vitro colony formation in response to GM-CSF. In addition, in a murine in vivo model of mbeta(c)-deficient PAP mbeta(c) gene transfer to hematopoietic stem cells not only restored the GM-CSF-sensitivity of hematopoietic progenitor cells but also, within a period of 12 weeks, almost completely reversed the morphologic features of surfactant accumulation. These results were obtained despite modest transduction levels (10-20%) and, in comparison to wild-type mice, clearly reduced beta(c) expression levels were detected in hematopoietic cells. Therefore, our data demonstrating genetic and functional correction of mbeta(c)(-/-) deficiency in vitro as well as in a murine in vivo model of PAP strongly suggest gene therapy as a potential new treatment modality in beta(c)-deficient PAP.
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PMID:Gene therapy of beta(c)-deficient pulmonary alveolar proteinosis (beta(c)-PAP): studies in a murine in vivo model. 1833 84

Systemic and inhalation therapy of granulocyte-macrophage colony-stimulating factor (GM-CSF) is usually effective in controlling autoimmune pulmonary alveolar proteinosis (PAP), but some cases are refractory to GM-CSF therapy and subjected to whole lung lavage (WLL). A 9-year-old girl developed severe respiratory failure due to autoimmune PAP was treated with inhalational 250 microg of GM-CSF daily, however, it was ineffective. Unilateral WLL was performed three times and subsequent GM-CSF inhalation therapy yielded marked physiological and radiological improvement and was continued for 1 year.
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PMID:A combination therapy of whole lung lavage and GM-CSF inhalation in pulmonary alveolar proteinosis. 1861 17

The acquired form of pulmonary alveolar proteinosis was determined in 3 patients, a woman of 31 and 2 men of48 and 38 years, respectively. Their symptoms consisted of progressive dyspnoea, with or without coughing and a tight feeling in the chest. Bronchoscopy with bronchoalveolar lavage yielded milky white, frothy material, and high resolution CT revealed parenchymal densification. All 3 patients were successfully treated with recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF; sargramostim); in addition, the first and last patient underwent total pulmonary lavage. During the pregnancy of the woman, the GM-CSF treatment was suspended; this was resumed after parturition, which took place via caesarean section. Pulmonary alveolar proteinosis is a rare disease characterised by accumulation of surfactant in the alveoli. Until recently, the treatment consisted only of total lung lavage under general anaesthesia. It has recently been discovered that IgG autoantibodies play an important role in the development ofthe disease, namely in the accumulation of surfactant in the alveoli. IgG autoantibodies appear to neutralise the biological activity of natural GM-CSF, which leads to accumulation of used surfactant in the alveoli and a decrease of the pulmonary diffusion capacity. These cases and other publications from the past few years underline the important role of GM-CSF, in addition to a total lung lavage, in the treatment of pulmonary alveolar proteinosis.
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PMID:[Pulmonary alveolar proteinosis: a disease caused by surfactant accumulation, and new treatment with sargramostim]. 1866 60

To describe the clinical, radiological and pathological characteristics of idiopathic pulmonary alveolar proteinosis (I-PAP) and to evaluate the methods of diagnosis and treatment. Three patients were successfully diagnosed and treated in our hospital and the literature on the subject was reviewed. Three patients, two males and one female (mean age 46 years), were diagnosed averagely in 4 months. Two severe patients presented with progressive dyspnea and type I respiratory failure, and one mild patient only with dry cough and hypoxemia. Chest X-ray radiographs all showed perihilar "butterfly" shadow and chest CT scans showed diffused ground-glass opacities (GGO), typically with "map" changes and "crazy paving" patterns. All the patients underwent bronchoscope, branchoalveolar lavage fluid (BALF) had grossly opaque and/or milky appearance and its sediment was periodic acid-Schiff stain positive. Trans-bronchoscopic lung biopsy (TBLB) specimens were obtained and under light microscopy alveoli and some of the small bronchioles were filled with eosinophilic proteinaceous material with needle-like clefts. By electron microscopy numerous cellular debris and extracellular multilamellated bodies were found. Two severe patients were successfully treated with sequential whole-lung lavage and one required repeated lavages. I-PAP is rare and prone to be misdiagnosed. The radiological features may indicate the diagnosis and examinations of TBLB and BALF can make the accurate diagnosis. Whole-lung lavage is the most effective therapy by now and granulocyte-macrophage colony-stimulating factor (GM-CSF) may be beneficial in some patients.
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PMID:[Idiopathic pulmonary alveolar proteinosis: report of three cases and literature review]. 1893 23


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