Chronic alcohol ingestion alters claudin expression in the alveolar epithelium of rats
Chronic alcohol ingestion alters claudin expression in the alveolar epithelium of rats
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DOI：
10.1016/j.alcohol.2007.04.010
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发表时间：
2007-08-01
期刊：
影响因子：
2.3
通讯作者：
Guidot, David M.
中科院分区：
文献类型：
--
作者：
Fernandez, Alberto L.;Koval, Michael;Guidot, David M.
先前，我们确定大鼠慢性酒精摄入（6周）增加肺上皮细胞的渗透性在体内类似5-6倍，并促进肺泡气腔的蛋白质液体的洪水响应于应激，如败血症。同时，从酒精喂养的大鼠中分离的肺泡上皮细胞在体外不能形成紧密的单层，即使在没有酒精的情况下培养长达8天。然而，酒精诱导的渗透性的分子机制是未知的。紧密连接蛋白是紧密连接的关键组成部分，其限制水、蛋白质和溶质跨细胞屏障（包括肺泡上皮）的细胞旁运动。在这项研究中，我们研究了多个成员的claudin蛋白质家族的表达，在肺中的酒精喂养与对照喂养的大鼠（Lieber-DeCarli液体饮食，无论是36%的热量作为酒精或等热量的替代品与麦芽糖糊精6周）。我们确定，慢性酒精摄入影响多种claudins的表达，最引人注目的是减少claudin-1和claudin-7，并增加claudin-5，在整个肺和肺泡上皮细胞单层来自酒精喂养的大鼠。与此同时，免疫细胞化学的肺泡上皮细胞单层从酒精喂养的大鼠发现异常细胞内聚集的claudin-7蛋白和相对减少的定位到细胞膜。紧密连接蛋白-1和紧密连接蛋白-7相对特异于形成体内绝大多数肺泡上皮屏障的肺泡上皮I型肺细胞，并且紧密连接蛋白-5的增加与其他系统中增加的上皮渗透性相关。因此，这些研究结果表明，在肺泡上皮细胞中的claudin表达的变化产生了一个“泄漏”的表型，使酒精肺在急性炎症应激过程中容易受到肺泡洪水。(C)2007年爱思唯尔公司All rights reserved.
Previously we determined that chronic alcohol ingestion (6 weeks) in rats increases lung epithelial permeability in vivo similar to 5-6-fold and promotes flooding of the alveolar airspaces with proteinaceous fluid in response to stresses such as sepsis. In parallel, alveolar epithelial cells isolated from alcohol-fed rats fail to form tight monolayers in vitro, even when cultured for up to 8 days in the absence of alcohol. However, the molecular mechanisms underlying alcohol-induced permeability are unknown. Claudins are key components of tight junctions that restrict the paracellular movement of water, proteins, and solutes across cellular barriers including the alveolar epithelium. In this study, we examined the expression of multiple members of the claudin protein family in the lungs of alcohol-fed versus control-fed rats (Lieber-DeCarli liquid diet with either 36% of calories as alcohol or an isocaloric substitution with maltin-dextrin for 6 weeks). We determined that chronic alcohol ingestion affected the expression of multiple claudins; most striking were decreases in claudin-1 and claudin-7, and an increase in claudin-5, in the whole lung and in alveolar epithelial monolayers derived from alcohol-fed rats. In parallel, immunocytochemistry of alveolar epithelial monolayers from alcohol-fed rats revealed abnormal intracellular accumulation of claudin-7 protein and relatively decreased localization to cell membranes. Claudin-1 and claudin-7 are relatively specific to alveolar epithelial type I pneumocytes that form the vast majority of the alveolar epithelial barrier in vivo, and increases in claudin-5 have been associated with increased epithelial permeability in other systems. Therefore, these findings suggest that changes in claudin expression in the alveolar epithelium produce a "leakier" phenotype that renders the alcoholic lung susceptible to alveolar flooding during acute inflammatory stresses. (C) 2007 Elsevier Inc. All rights reserved.