Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
 6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Macrophages exist in almost all animals. In some invertebrates, mesenchymal cells, endothelial cells or fibroblast-like cells can transform into macrophages. In vertebrates, primitive macrophages first develop in yolk sac hematopoiesis and differentiate into fetal macrophages. Monocytes are differentiated from hematopoietic stem cells in the late stage of fetal hematopoietic organs and bone marrow. Macrophages serve as an effector in metabolism and host defense. Depletion of macrophages severely reduced bilirubin production and host resistance to infection. Macrophage scavenger receptors are involved in host defense. Macrophage growth factors are critical for macrophage differentiation and function. In macrophage colony-stimulating factor (M-CSF)-deficient osteopetrotic mice, monocytes, tissue macrophages and osteoclasts are deficient. Granulocyte-macrophage colony-stimulating factor (GM-CSF)-deficient mice develop alveolar proteinosis due to impaired surfactant catabolism by alveolar macrophages. Accumulation of glucocerebroside in macrophages due to the deficiency of glucocerebrosidase in lysosomes produces Gaucher cells. Macrophages in the arterial wall incorporate chemically modified low-density lipoprotein (LDL) and transform into foam cells. Binding oxidized LDL to liver X receptor alpha (LXRalpha) upregulates the expression of its target genes, which act as cholesterol removers from macrophages. Inflammatory signals downregulate the expression of LXRalpha and enhance lipid accumulation. Thus, macrophages play a pivotal role in metabolism and host defense.
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PMID:Macrophage differentiation and function in health and disease. 1825 77