Chronic ethanol ingestion in rats decreases granulocyte-macrophage colony-stimulating factor receptor expression and downstream signaling in the alveolar macrophage
Chronic ethanol ingestion in rats decreases granulocyte-macrophage colony-stimulating factor receptor expression and downstream signaling in the alveolar macrophage
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DOI：
10.4049/jimmunol.175.10.6837
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发表时间：
2005-11-15
影响因子：
4.4
通讯作者：
Guidot, DM
中科院分区：
文献类型：
--
作者：
Joshi, PC;Applewhite, L;Guidot, DM
虽然酒精滥用损害肺泡巨噬细胞免疫功能并使患者易患肺炎是众所周知的，但其机制尚不完全清楚。肺泡巨噬细胞的成熟和功能需要GM-CSF的启动，GM-CSF由肺泡上皮产生并分泌到肺泡间隙。在本研究中，我们确定，尽管大鼠慢性摄入乙醇（6周）对肺泡间隙内GM-CSF表达没有影响，但它显著降低了肺泡巨噬细胞中GM-CSF受体的膜表达。同时，乙醇摄入降低了细胞表达和PU.1的核结合，PU.1是激活gm - csf依赖性巨噬细胞功能的主转录因子。此外，经上气道给乙醇喂养的大鼠体内注入rGM-CSF，恢复了GM-CSF受体膜表达、肺泡巨噬细胞中PU.1蛋白表达和核结合。重要的是，GM-CSF治疗还恢复了乙醇喂养大鼠的肺泡巨噬细胞功能，这反映在内毒素刺激的tnf - α释放和细菌吞噬作用上。我们得出结论，乙醇摄入通过降低GM-CSF受体表达和下游PU.1核结合来抑制肺泡巨噬细胞的免疫功能，这些慢性缺陷可以在体内通过rGM-CSF治疗相对较快地逆转。
Although it is well recognized that alcohol abuse impairs alveolar macrophage immune function and renders patients susceptible to pneumonia, the mechanisms are incompletely understood. Alveolar macrophage maturation and function requires priming by GM-CSF, which is produced and secreted into the alveolar space by the alveolar epithelium. In this study, we determined that although chronic ethanol ingestion (6 wk) in rats had no effect on GM-CSF expression within the alveolar space, it significantly decreased membrane expression of the GM-CSF receptor in alveolar macrophages. In parallel, ethanol ingestion decreased cellular expression and nuclear binding of PU.1, the master transcription factor that activates GM-CSF-dependent macrophage functions. Furthermore, treatment of ethanol-fed rats in vivo with rGM-CSF via the upper airway restored GM-CSF receptor membrane expression as well as PU.1 protein expression and nuclear binding in alveolar macrophages. Importantly, GM-CSF treatment also restored alveolar macrophage function in ethanol-fed rats, as reflected by endotoxin-stimulated release of TNF-alpha and bacterial phagocytosis. We conclude that ethanol ingestion dampens alveolar macrophage immune function by decreasing GM-CSF receptor expression and downstream PU.1 nuclear binding and that these chronic defects can be reversed relatively quickly with rGM-CSF treatment in vivo.