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)

Mutation of the granulocyte-macrophage colony-stimulating factor (GM-CSF) gene by homologous recombination caused alveolar proteinosis in mice. To further discern the role of GM-CSF in surfactant homeostasis, the synthesis of GM-CSF was directed to the respiratory epithelium of GM-CSF-hull mutant mice (GM-/-) with a chimeric gene expressing GM-CSF under the control of the promoter from the human surfactant protein-C (SP-C) gene. Transgenic mice bearing the SP-C-GM-CSF construct (SP-C-GM+) were bred to GM-/- mice resulting in complete correction of alveolar proteinosis in bitransgenic GM-/-, SP-C-GM+ mice. No effects of the transgene were found outside the lung. GM-CSF was increased in bronchoalveolar lavage fluid of the bitransgenic mice. Surfactant proteins-A and -B and phospholipid in bronchoalveolar lavage fluid were normalized in the GM-/-, SP-C-GM+ mice. SP-A, -B, and -C mRNAs were unaltered in lungs from GM-CSF-deficient and -replete mice. Expression of GM-CSF in respiratory epithelial cells of transgenic mice restores surfactant homeostasis in GM-/- mice. From these findings, we conclude that GM-CSF regulates the clearance or catabolism rather than synthesis of surfactant proteins and lipids.
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PMID:Pulmonary epithelial cell expression of GM-CSF corrects the alveolar proteinosis in GM-CSF-deficient mice. 860 11

Pulmonary alveolar proteinosis (PAP) is caused by inactivation of either granulocyte-macrophage colony-stimulating factor (GM-CSF) or GM receptor common beta-chain (beta(c)) genes in mice [GM(-/-), beta(c)(-/-)], demonstrating a critical role of GM-CSF signaling in surfactant homeostasis. To distinguish possible phenotypic differences in GM(-/-) and beta(c)(-/-) mice, surfactant metabolism was compared in beta(c)(-/-), GM(-/-), and wild-type mice. Although lung histology in beta(c)(-/-) and GM(-/-) mice was indistinguishable, distinct differences were observed in surfactant phospholipid and surfactant protein concentrations and clearance from lungs of beta(c)(-/-) and GM(-/-) mice. At 1-2 days of age, lung saturated phosphatidylcholine (Sat PC) pool sizes were higher in wild-type, beta(c)(-/-), and GM(-/-) mice compared with wild-type adult mice. In wild-type mice, Sat PC pool sizes decreased to adult levels by 7 days of age; however, Sat PC increased with advancing age in beta(c)(-/-) and GM(-/-) mice. Postnatal changes in Sat PC pool sizes were different in GM(-/-) compared with beta(c)(-/-) mice. After 7 days of age, the increased lung Sat PC pool sizes remained constant in beta(c)(-/-) mice but continued to increase in GM(-/-) mice, so that by 56 days of age, lung Sat PC pools were increased three- and sixfold, respectively, compared with wild-type controls. After intratracheal injection, the percent recovery of [(3)H]dipalmitoylphosphatidylcholine and (125)I-recombinant surfactant protein (SP) C was higher in beta(c)(-/-) compared with wild-type mice, reflecting decreased clearance in the receptor-deficient mice. The defect in clearance was significantly more severe in GM(-/-) than in beta(c)(-/-) mice. The ratio of SP Sat PC to SP-A, -B, and -C was similar in bronchoalveolar lavage fluid (BALF) from adult mice of all genotypes, but the ratio of SP-D to Sat PC was markedly increased in beta(c)(-/-) and GM(-/-) mice (10- and 5-fold, respectively) compared with wild-type mice. GM-CSF concentrations were increased in BALF but not in serum of beta(c)(-/-) mice, consistent with a pulmonary response to the lack of GM-CSF signaling. The observed differences in surfactant metabolism suggest the presence of alternative clearance mechanisms regulating surfactant homeostasis in beta(c)(-/-) and GM(-/-) mice and may provide a molecular basis for the range in severity of PAP symptoms. surfactant metabolism; alveolar macrophage; granulocyte-macrophage colony-stimulating factor
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PMID:Distinct changes in pulmonary surfactant homeostasis in common beta-chain- and GM-CSF-deficient mice. 1083 21

Mice deficient in surfactant protein (SP) D develop increased surfactant pool sizes and dramatic changes in alveolar macrophages and type II cells. To test the hypothesis that granulocyte-macrophage colony-stimulating factor (GM-CSF) mediates alveolar macrophage proliferation and activation and the type II cell hypertrophy seen in SP-D null mice, we bred SP-D and GM-CSF gene-targeted mice to obtain littermate double null, single null, and wild-type mice. Bronchoalveolar lavage levels of phospholipid, protein, SP-D, SP-A, and GM-CSF were measured from 1 to 4 mo. There was an approximately additive accumulation of phospholipid, total protein, and SP-A at each time point. Microscopy showed normal macrophage number and morphology in GM-CSF null mice, numerous giant foamy macrophages and hypertrophic type II cells in SP-D null mice, and large but not foamy macrophages and mostly normal type II cells in double null mice. These results suggest that the mechanisms underlying the alveolar surfactant accumulation in the SP-D-deficient and GM-CSF-deficient mice are different and that GM-CSF mediates some of the macrophage and type II cell changes seen in SP-D null mice.
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PMID:GM-CSF mediates alveolar macrophage proliferation and type II cell hypertrophy in SP-D gene-targeted mice. 1135 Jul 93

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

We treated 8 cases of autoimmune pulmonary alveolar proteinosis (APAP) with whole lung lavage (WLL) in our hospital and evaluated the disease severity of APAP before and after WLL, adverse events (AEs) and recurrence-free survival in those cases who improved. In all cases, unilateral WLL was performed in both lungs. The median of total lavage volume in unilateral WLL was 17.9 L, and the median procedure time of unilateral WLL was 105 min. Fever was the most frequently observed AE (87.5% of all procedures). Pulmonary function tests (percentage of predicted value of VC, FEV1 and diffusing capacity of carbon monoxide), serum markers (KL-6, surfactant apoprotein (SP)-D, SP-A and carcinoembryonic antigens), arterial blood gas analyses (PaO2, AaDO2) and disease severity score all significantly improved after WLL. The serum levels of anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibody temporarily decreased after unilateral WLL, but returned to previous levels (before WLL) in 7 cases. The radiological findings improved in 6 cases. In the 7 improved cases in whom AaDO2 decreased more than 10 Torr, the median recurrence-free survival of APAP after WLL was 17.5 months. We concluded that WLL is an effective and safe method for the treatment of APAP, and all parameters except for anti GM-CSF antibody are useful to evaluate the effect of WLL.
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PMID:[Multidisciplinary assessment of effects, safety and procedure of whole lung lavage for 8 patients with autoimmune pulmonary alveolar proteinosis]. 2189 71

Pulmonary surfactant is essential for life as it lines the alveoli to lower surface tension, thereby preventing atelectasis during breathing. Surfactant is enriched with a relatively unique phospholipid, termed dipalmitoylphosphatidylcholine, and four surfactant-associated proteins, SP-A, SP-B, SP-C, and SP-D. The hydrophobic proteins, SP-B and SP-C, together with dipalmitoylphosphatidylcholine, confer surface tension-lowering properties to the material. The more hydrophilic surfactant components, SP-A and SP-D, participate in pulmonary host defense and modify immune responses. Specifically, SP-A and SP-D bind and partake in the clearance of a variety of bacterial, fungal, and viral pathogens and can dampen antigen-induced immune function of effector cells. Emerging data also show immunosuppressive actions of some surfactant-associated lipids, such as phosphatidylglycerol. Conversely, microbial pathogens in preclinical models impair surfactant synthesis and secretion, and microbial proteinases degrade surfactant-associated proteins. Deficiencies of surfactant components are classically observed in the neonatal respiratory distress syndrome, where surfactant replacement therapies have been the mainstay of treatment. However, functional or compositional deficiencies of surfactant are also observed in a variety of acute and chronic lung disorders. Increased surfactant is seen in pulmonary alveolar proteinosis, a disorder characterized by a functional deficiency of the granulocyte-macrophage colony-stimulating factor receptor or development of granulocyte-macrophage colony-stimulating factor antibodies. Genetic polymorphisms of some surfactant proteins such as SP-C are linked to interstitial pulmonary fibrosis. Here, we briefly review the composition, antimicrobial properties, and relevance of pulmonary surfactant to lung disorders and present its therapeutic implications.
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PMID:The Role of Surfactant in Lung Disease and Host Defense against Pulmonary Infections. 2574 23