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)

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

Both surfactant protein (SP) D and granulocyte-macrophage colony-stimulating factor (GM-CSF) influence pulmonary surfactant homeostasis, with the deficiency of either protein causing marked accumulation of surfactant phospholipids in lung tissues and in the alveoli. To assess whether the effects of each gene were mediated by distinct or shared mechanisms, surfactant homeostasis and lung morphology were assessed in 1) double-transgenic mice in which both SP-D and GM-CSF genes were ablated [SP-D(-/-),GM(-/-)] and 2) transgenic mice deficient in both SP-D and GM-CSF in which the expression of GM-CSF was increased in the lung. Saturated phosphatidylcholine (Sat PC) pool sizes were markedly increased in SP-D(-/-),GM(-/-) mice, with the effects of each gene deletion on surfactant Sat PC pool sizes being approximately additive. Expression of GM-CSF in lungs of SP-D(-/-),GM(-/-) mice corrected GM-CSF-dependent abnormalities in surfactant catabolism but did not correct lung pathology characteristic of SP-D deletion. In contrast to findings in GM(-/-) mice, degradation of [(3)H]dipalmitoylphosphatidylcholine by alveolar macrophages from the SP-D(-/-) mice was normal. The emphysema and foamy macrophage infiltrates characteristic of SP-D(-/-) mice were similar in the presence or absence of GM-CSF. Taken together, these findings demonstrate the distinct roles of SP-D and GM-CSF in the regulation of surfactant homeostasis and lung structure.
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PMID:SP-D and GM-CSF regulate surfactant homeostasis via distinct mechanisms. 1150 98

Existence of anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) neutralizing antibody and treatment with recombinant GM-CSF are new topics in idiopathic pulmonary alveolar proteinosis (PAP). We have hypothesized inhaled GM-CSF is effective and neutralizing capacity of GM-CSF, not concentration of anti-GM-CSF antibody in serum reflect disease severity. A 57-year-old female smoker with idiopathic PAP was treated with inhaled GM-CSF. The response to the treatment was evaluated by diffusing capacity for carbon monoxide (DLCO), alveolar-arterial oxygen gradient ([A-a]DO2). Conventional serum markers, including KL-6, surfactant apoprotein (SP)-A, SP-D, carcino-embryonic antigen and cytokeratin fragment 19 (CYFRA), and concentration of anti-GM-CSF antibody were examined. The neutralizing capacity of GM-CSF in serum was evaluated using a GM-CSF dependent cell line, TF-1. Ground glass opacity disappeared at the end of the treatment. Her DLCO, [A-a]DO2 remarkably improved after treatment. The neutralizing capacity of GM-CSF declined in line with disease remission and it correlated significantly with DLCO (P = 0.0137). The concentration of anti-GM-CSF antibody had no significant relation with disease severity and serum markers including neutralizing capacity. Conventional serum markers other than CYFRA showed no significant correlation with Inhaled GM-CSF was effective for idiopathic PAR Serial measurement of neutralizing capacity of GM-CSF was useful to evaluate disease severity and the anti-GM-CSF antibody was proved to be a causative factor for PAR In the future, inhaled GM-CSF may replace whole lung lavage and response to GM-CSF and its optimal amount may be decided by the capacity.
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PMID:Serum neutralizing capacity of GM-CSF reflects disease severity in a patient with pulmonary alveolar proteinosis successfully treated with inhaled GM-CSF. 1558 45

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 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