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)

A central factor in the pathogenesis of inflammatory and fibrotic lung disease (adult respiratory distress syndrome, sarcoidosis, idiopathic pulmonary fibrosis) is the locally elevated number of alveolar macrophages (AM). An elevation in the production rate of AM, chemoattraction and differentiation of monocytes, or a diminution in the death rate might be underlying mechanisms. The aim of the present study was to investigate the modulatory role of endotoxin and cytokines on the death rate of human AM. Lipopolysaccharide (LPS) treatment resulted in a 4-fold increase (7.6 to 30.2%) of AM death. AM death was apoptotic as assessed by in situ DNA end labeling (ISDE), transmission electron microscopy, DNA gel electrophoresis, fluorometry of fragmented DNA, and an ELISA specific for histone-associated DNA fragments. Among the different bacterial cell wall components tested, LPS was the only inducer of apoptosis in human AM. None of the tested cytokines (interleukin-1 beta [IL-1 beta], IL-4, IL-6, IL-10, tumor necrosis factor-alpha [TNF-alpha], transforming growth factor-beta 2 [TGF-beta 2], interferon-gamma [IFN-gamma], macrophage colony-stimulating factor [M-CSF], granulocyte colony-stimulating factor [G-CSF], and granulocyte-macrophage colony-stimulating factor [GM-CSF]) was capable of enhancing the spontaneous rate of apoptosis. However, LPS-induced apoptosis was significantly enhanced by the macrophage-activating cytokine IFN-gamma, and reduced by the macrophage-deactivating cytokines IL-4, IL-10, and TGF-beta.
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PMID:Apoptosis in human alveolar macrophages is induced by endotoxin and is modulated by cytokines. 867 23

Cystic fibrosis (CF) patients develop progressive cytokine-mediated inflammatory lung disease, with abundant production of thick, tenacious, protease- and oxidant-rich purulent airway secretions that are difficult to clear even with physiotherapy. In the search for a potential treatment, we have tested tyloxapol, an alkylaryl polyether alcohol polymer detergent previously used as a mucolytic agent in adult chronic bronchitis. Tyloxapol inhibits activation of the transcription factor nuclear factor-kappa B (NK-kappa B), reduces resting secretion of the cytokine interleukin-8 (IL-8) in cultured human monocytes, and inhibits lipopolysaccharide (LPS)-stimulated release of tumor necrosis factor-alpha (TNF-alpha), IL-1 beta, IL-6, IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF), and the eiconsanoids thromboxane A2 and leukotriene B4 (LTB4). We have previously shown that tyloxapol is a potent antioxidant for hydroxyl radicals ( OH). Tyloxapol (0.05 to 0.1% wt/vol) effectively scavenges the oxidant hypochlorous acid (HOCl; 1 to 7.5 mM) in vitro, and protects from HOCl-mediated lung injury in rats. Tyloxapol also reduces the viscosity of CF sputum (from 463 +/- 133 to 128 +/- 52 centipoise). We conclude that tyloxapol is potentially useful as a new antiinflammatory therapy for CF lung disease, and could possibly promote clearance of secretions in the CF airway.
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PMID:Tyloxapol inhibits NF-kappa B and cytokine release, scavenges HOCI, and reduces viscosity of cystic fibrosis sputum. 881 Jun 19

Deficiency of the granulocyte-macrophage colony-stimulating factor (GM-CSF)/interleukin-3 (IL-3)/IL-5 receptors common beta chain (betac) is a cause of fatal respiratory failure. betac deficiency manifests as pulmonary alveolar proteinosis (PAP). PAP has heterogenous etiologies that may be genetic or aquired. Some cases of PAP have been reported to be associated with hematologic malignancies such as acute myeloid leukemia (AML). In mice, the PAP phenotype was generated by targeted deletion of the gene for betac and can be treated by transplantation of wild-type bone marrow into betac -/- mice. Thus, our findings in betac -/- mice provide evidence for a causal relationship between the lung disease and the hematopoietic system. We describe here expression defects of betac or betac plus GM-CSF receptor alpha chain (GM-CSFR alpha) in 3 pediatric patients with AML and PAP symptoms. All of the patients' leukemic cells failed to express normal levels of betac. The leukemic cells of patients no. 2 and 3 additionally lacked the expression of GM-CSFR alpha, as shown by flow cytometry. Strikingly reduced or absent function of betac was demonstrated in clonogenic progenitor assays with absent colony-forming unit (CFU) growth after GM-CSF or IL-3 stimulation. The response to growth factors acting via a growth factor receptor distinct from the GM-CSF/IL-3/IL-5 system (recombinant human granulocyte colony-stimulating factor [rhG-CSF]) was normal. After antileukemic treatment, the pulmonary symptoms resolved and betac or betac plus GM-CSFR alpha expression was normal. Our findings provide evidence that a defect in the expression of betac or betac plus GM-CSFR alpha on AML blasts can be associated with respiratory failure in patients with AML.
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PMID:Defective expression of granulocyte-macrophage colony-stimulating factor/interleukin-3/interleukin-5 receptor common beta chain in children with acute myeloid leukemia associated with respiratory failure. 969 96

The pathogenesis of acquired pulmonary alveolar proteinosis (PAP), a rare lung disease characterized by excessive surfactant accumulation within the alveolar space, remains obscure. Gene-targeted mice lacking the hematopoietic growth factor granulocyte-macrophage colony-stimulating factor (GM-CSF) or the signal-transducing beta-common chain of the GM-CSF receptor have impaired surfactant clearance and pulmonary pathology resembling human PAP. We therefore investigated the hematopoietic effects of GM-CSF in patients with PAP. The hematologic response of 5 infants with congenital PAP to 5 microgram/kg/d was of normal magnitude. By contrast, despite normal expression of GM-CSF receptor alpha- and beta-common chains on peripheral blood myelomonocytic cells (n = 6) and normal binding affinity of bone marrow mononuclear cells for GM-CSF (n = 3), each of the 12 patients with acquired PAP treated displayed impaired responses to GM-CSF; 5 microgram/kg/d produced only minor eosinophilia, and doses of 7.5 to 20 microgram/kg were required to induce >/=1.5-fold neutrophil increments in the 3 patients who underwent dose-escalation. However, neutrophilic responses to 5 microgram/kg granulocyte colony-stimulating factor (G-CSF) were normal (n = 4). In vitro, the proportion of hematopoietic progenitors responsive to GM-CSF (16.1% +/- 8.9%; P = .042) or interleukin-3 (IL-3; 19.3% +/- 7.7%; P = .063), both of which utilize the beta-common chain of the GM-CSF receptor complex, were reduced among patients with acquired PAP (n = 4) compared with normal bone marrow donor controls (47.2% +/- 25.9% and 40.9% +/- 18.6%, respectively). In the one individual who had complete resolution of lung disease during the period of study, this was temporally associated with correction of this defective in vitro response to GM-CSF and IL-3 on serial assessment. These data establish that patients with acquired PAP have an associated impaired responsiveness to GM-CSF that is potentially pathogenic in the development of their lung disease. Based on these observations, we propose a model of the pathogenesis of acquired PAP that suggests the disease arises as a consequence of an acquired clonal disorder within the hematopoietic progenitor cell compartment.
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PMID:Attenuated hematopoietic response to granulocyte-macrophage colony-stimulating factor in patients with acquired pulmonary alveolar proteinosis. 976 47

Mice with a null mutation of the betac chain of the granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and IL-5 receptors (betac-null mice) develop an alveolar proteinosis-like lung disease. The pathogenesis of this disease is uncertain and, although a defect in alveolar macrophage function has been postulated, no previous analysis of mature hematopoietic cells in mice with alveolar proteinosis has been reported. Therefore, we undertook a functional analysis of the mature hematopoietic cell compartment in betac-null mice. In addition, we reexamined the roles of the GM-CSF receptor chain and the betac chain in signaling by GM-CSF. Neutrophils and macrophages from betac-null mice were capable of normal survival and phagocytosis in the absence of stimulus and of similar levels of nitric oxide production in response to interferon-gamma and lipopolysaccharide. GM-CSF-mediated augmentation of survival, phagocytosis, and hydrogen-ion production were absent in neutrophils from betac-null mice. Interestingly, we were unable to show any ability of the GM-CSF receptor -chain alone to mediate glucose transport in these cells. In keeping with the betac-null mice lung pathology, examination of lavage fluid from the lungs of betac-null mice showed increased cellularity. This was caused by an increase in the number of lymphocytes, neutrophils, and macrophages. Large foamy cells in the lavage fluid from betac-null mice were identified as macrophages using immunohistochemistry. Functional analysis showed that these betac-null alveolar macrophages were capable of phagocytosis but uptake of colloidal carbon and cellular adhesion were reduced. In summary, mature hematopoietic cells with a null mutation of the betac receptor were unable to perform GM-CSF-mediated hematopoietic cell functions including glucose transport, but responded normally to a range of other ligands.
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PMID:Functional analysis of mature hematopoietic cells from mice lacking the betac chain of the granulocyte-macrophage colony-stimulating factor receptor. 983 17

The hematopoietic cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF), Interleukin (IL)-5 and IL-3 utilise a common receptor signalling molecule, the beta common chain (beta c). This shared receptor component explains, in part the overlapping actions of these cytokines. Mice lacking beta c have a low circulating eosinophil level, have impaired eosinophilic responses to parasitic infection and develop lung disease analogous to human pulmonary alveolar proteinosis (PAP). Surprisingly however, mature hematopoietic cell function is relatively intact, although all GM-CSF-mediated mature cell responses, including glucose transport are absent. Intriguing observations suggesting altered susceptibility to some infectious agents and amelioration of responses to inflammatory stimuli, require further clarification.
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PMID:The beta common chain (beta c) of the granulocyte macrophage-colony stimulating factor, interleukin-3 and interleukin-5 receptors. 1058 35

The relationship of serum human immunodeficiency virus-1 (HIV-1) RNA levels to HIV-1 RNA levels in other compartments, such as the lungs, is not well characterized. The purpose of this study was to determine the viral burden of HIV-1 in the lungs by comparing HIV-1 RNA in cell-free bronchoalveolar lavage fluid (BALF) with that in serum. Specimens were examined from 77 HIV-seropositive adults (CD4(+) cell counts: 0 to 700 cells/mm(3); 48% receiving prescribed antiretroviral agents), comprising 43 asymptomatic individuals who were compared with 34 persons with active lung disease caused by Pneumocystis carinii (n = 26), bacteria (n = 3), Mycobacterium avium complex (n = 2), Nocardia sp. (n = 1), Aspergillus sp. (n = 1), or pulmonary Kaposi's sarcoma (n = 1). For serum HIV-1 RNA, the proportion of subjects with detectable levels and the mean values were similar for asymptomatic individuals and persons with active lung disease (85% versus 86%, respectively) (6.64 x 10(4) versus 1. 81 x 10(5) HIV-1 RNA copies/ml; p = 0.13). In contrast, HIV-1 RNA in BALF was more often detected (16% versus 62%; p = 0.001), and mean values were higher (1.04 x 10(5) versus 3.31 x 10(6) HIV-1 RNA copies/ml; p = 0.032), in subjects with active lung disease than in asymptomatic subjects, independent of early or advanced clinical stages of HIV-related disease. For both study groups, HIV-1 RNA levels in BALF exceeded those in serum in 56% of cases by up to 66-fold, and did not correlate with local levels of tumor necrosis factor-alpha, granulocyte-macrophage colony-stimulating factor, or interleukin-16. HIV-1 proviral DNA in cells from BALF was detected in up to 86% of subjects, more frequently in persons with advanced HIV disease (p = 0.0496), and often involved > 10% of BALF cells, but did not correlate with HIV-1 RNA detected in BALF. These data provide evidence for active HIV-1 replication in the lungs. HIV-1 replication is compartmentalized relative to serum, may be restricted, is independent of HIV-1 proviral DNA and clinical stage of HIV, and may be influenced by pulmonary disease such as P. carinii pneumonia or by other local or lung-specific factors. The lungs represent a large reservoir for HIV-1, and may present a source of persistent HIV-1 replication even during periods of apparent clinical latency of HIV-1 infection.
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PMID:Enhanced in vivo human immunodeficiency virus-1 replication in the lungs of human immunodeficiency virus-infected persons with Pneumocystis carinii pneumonia. 1058 27

Pulmonary alveolar proteinosis (PAP) is an idiopathic lung disease in which the alveolar spaces are filled with surfactant. Recently, it has been proposed that PAP is caused by deficiency of granulocyte-macrophage colony-stimulating factor (GM-CSF) because GM-CSF-knockout mice develop the disease. To examine this possibility, we tested the two hypotheses that lung GM-CSF levels are low and that alveolar macrophages (AM) do not respond to GM-CSF in patients with PAP. Data from 10 adult patients with PAP who underwent therapeutic whole-lung lavage were compared with those of 10 healthy volunteers who underwent bronchoalveolar lavage (BAL) by fiberoptic bronchoscopy. Bronchoalveolar lavage fluid (BALF) and plasma were collected and analyzed for total protein and levels of GM-CSF, interleukin-3, and tumor necrosis factor (TNF)-alpha. Isolated AM were cultured with or without lipopolysaccharide (LPS) or GM-CSF, and production of GM-CSF and TNF-alpha was measured after 24 h. GM-CSF in BALF and plasma was higher in PAP than in control subjects (p </= 0.05), and was detectable under both reducing and nonreducing conditions as a 28-kD protein in BALF from the PAP patients. GM-CSF release by unstimulated AM from PAP patients was higher than in cells from control subjects, but the responses to LPS were similar. Mean TNF-alpha release by AM in response to GM-CSF was higher in control subjects than in PAP patients due to a low response in three patients. In conclusion, unbound immunoreactive GM-CSF is detectable in BALF and plasma of PAP patients. Most PAP patients also had intact AM responses to GM-CSF, although some may have had defects in GM-CSF receptor or signal-transduction mechanisms. Although these data exclude lack of GM-CSF production as a common etiology of human PAP, defects in GM-CSF function in PAP are under investigation.
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PMID:Detection of granulocyte-macrophage colony-stimulating factor in patients with pulmonary alveolar proteinosis. 1076 26

Continued definition of the biochemical and molecular mechanisms underlying the development of chronic lung disease (CLD) has persuaded investigators that inflammatory cells and mediators are key factors in the pathophysiology of the disease. High numbers of inflammatory cells and their products are present in the airways of ventilated neonates with respiratory distress syndrome and precede the development of CLD. This article reviews the mechanisms underlying neutrophil recruitment in the lungs of ventilated preterm infants with respiratory distress syndrome and the injurious effects that these cells can produce on lung parenchyma with special emphasis on the development of CLD. The role of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor is stressed as a pivotal mechanism of neutrophil recruitment and activation.
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PMID:Infection, neutrophils, and hematopoietic growth factors in the pathogenesis of neonatal chronic lung disease. 1098 37

Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been shown to play a protective role in leishmanial infection. Mice with a null mutation in the gene for the beta common (beta c) chain of the receptors for GM-CSF, interleukin(IL)-3 and IL-5 (beta c-null mice) display normal steady state hemopoiesis and develop lung disease similar to the human condition, alveolar proteinosis, due to a lack of signaling by GM-CSF. We therefore expected to observe a heightened sensitivity to Leishmania major in the beta c-null mice. Surprisingly, the beta c-null mice were more resistant to cutaneous infection than wild-type (wt) mice. Upon intradermal injection of L. major promastigotes, fewer beta c-null mice developed cutaneous lesions than wt mice and these lesions were smaller and healed more rapidly than in wt mice. This resistance to disease was associated with a reduced percentage of in vitro infected beta c-null macrophages. Macrophages from beta c-null mice displayed a more activated phenotype and produced increased amounts of nitric oxide following infection with L. major, both in vivo and in vitro. Paradoxically, however, the parasite burden in the draining lymph nodes was similar in both beta c-null and wt mice, suggesting that at least a subpopulation of cells was susceptible to the parasite. The mechanism preventing normal lesion development remains to be elucidated.
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PMID:Mice unresponsive to GM-CSF are unexpectedly resistant to cutaneous Leishmania major infection. 1100 3


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