Impaired Terminal Differentiation of Pulmonary Macrophages in a Guinea Pig Model of Chronic Ethanol Ingestion
Impaired Terminal Differentiation of Pulmonary Macrophages in a Guinea Pig Model of Chronic Ethanol Ingestion
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DOI：
10.1111/j.1530-0277.2009.01017.x
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发表时间：
2009-10-01
影响因子：
3.2
通讯作者：
Brown, Lou Ann S.
中科院分区：
文献类型：
--
作者：
Brown, Sheena D.;Gauthier, Theresa W.;Brown, Lou Ann S.
背景：酒精患者呼吸道感染的风险增加，部分原因是肺泡巨噬细胞免疫反应受损。酒精损害肺泡巨噬细胞功能的机制尚不清楚。在这项研究中，我们在豚鼠模型中证明了慢性乙醇摄入显著损害肺泡巨噬细胞分化和功能。方法：将分离的肺泡巨噬细胞分为4个不同密度和成熟程度的亚群。结果：与对照组相比，慢性乙醇摄入可使成熟部位肺泡巨噬细胞百分比降低约60%。通过测量异硫氰酸荧光素标记的金黄色葡萄球菌的吞噬作用来确定每个亚群的肺泡巨噬细胞功能。乙醇喂养动物肺泡巨噬细胞的吞噬指数下降了80%。Western blot和免疫组织化学分析差异标记粒细胞/巨噬细胞集落刺激因子（GM-CSF）受体α (GM-CSF - α)、PU.1、CD11c和CD11b证实酒精性巨噬细胞表现出终端分化受损。虽然口服谷胱甘肽前体s -腺苷蛋氨酸（SAM）没有改变对照动物的成熟状态，但SAM的补充使巨噬细胞的分布向更成熟的部分转移，使吞噬指数正常化；以及CD11c、CD11b、PU.1和gm - csf -alpha的归一化表达。慢性乙醇摄入也会损害间质巨噬细胞的分化状态，而这种分化状态通过补充SAM而正常化。结论：这种成熟状态的改善表明，乙醇诱导的氧化应激是巨噬细胞间质和肺泡间隙末端分化受损的核心特征。因此，针对肺氧化应激的策略可以恢复巨噬细胞的分化和功能，即使在慢性乙醇摄入后。
Background:Alcoholic patients have an increased risk of respiratory infections, which is partially due to an impaired immune response of alveolar macrophages. The mechanisms by which alcohol impairs alveolar macrophage function are poorly understood. In this study, we demonstrated in a guinea pig model that chronic ethanol ingestion significantly impaired alveolar macrophage differentiation and function.Methods:Isolated alveolar macrophages were separated into 4 different subpopulations with varying densities and levels of maturation.Results:Compared to control values, chronic ethanol ingestion decreased the percentage of alveolar macrophages in the mature fractions by similar to 60%. Alveolar macrophage function in each subpopulation was determined by measuring phagocytosis of fluorescein isothiocyanate-labeled Staphylococcus aureus. Alveolar macrophages from ethanol-fed animals had similar to 80% decrease in the phagocytic index. Western blot and immunohistochemical analysis of the differential markers granulocyte/macrophage colony-stimulating factor (GM-CSF) receptor alpha (GM-CSFR-alpha), PU.1, CD11c, and CD11b verified that alcoholic macrophages displayed impaired terminal differentiation. While oral supplementation with the glutathione precursor S-adenosyl-methionine (SAM) did not alter the maturational status of control animals, SAM supplementation shifted the distribution of macrophages to more mature fractions, normalized the phagocytic index; as well as normalized expression of CD11c, CD11b, PU.1, and GM-CSFR-alpha. Chronic ethanol ingestion also impaired the differentiation status of interstitial macrophages which was normalized by SAM supplementation.Conclusion:This improvement in the maturational status suggested that ethanol-induced oxidant stress is a central feature in impaired terminal differentiation of macrophages in the interstitial and alveolar space. Therefore, strategies targeting pulmonary oxidant stress may restore macrophage differentiation and function even after chronic ethanol ingestion.