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Airway epithelical Cl channel regulation by iNOS gene

iNOS 基因对气道上皮 Cl 通道的调节

基本信息

批准号：
10670563
负责人：
TAMAOKI Jun
金额：
$ 1.92万
依托单位：
Tokyo Women's Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670563/
关键词：
Airway epithelium Nitric oxide Ion channel Patch clamp Gene expression Airway secretion Airway inflammation Asthma 気道分必

项目摘要

There is increasing evidence that nitric oxide (NO) is synthesized and released in the airways, thereby playing a role in a variety of airway functions. In the present experiment, to determine whether epithelium-derived NO is involved in the regulation of Cl secretion and, hence, water secretion into the airway lumen, we studied isolated human bronchial epithelial cells in vitro. Patch clamp studies of isolated airway epithelium showed that intracellular adition of high calcium solution plus bradykinin, or the NO donors S-nitroacetyl-N-penicillamine and nitroprusside caused an increase in Cl-selective current and open probability of luminal Cl channel. This effect was accompanied by the corresponding increase in NO-selective electrical current, as measured by a polarography using an NO-selective electrode, and induction of the presence of constitutive NO synthase (cNOS)-like immunoreactivities. On the other hand, stimulation of the cells with endotoxin from E. coli, interleukin-1β, tumor necrosis factor-α, or interferon-γ each increased Cl conductance and single Cl channel current. This effect was likewise accompanied by the increase in NO concentration in the medium, but, based on Nothern analysis and immunocytochemistry, expressions of iNOS mRNA and iNOS protein were upregulated by these stimuli. Futhermore,these effects were dose-dependently inhibited by 14-membered macrolides and glucocorticosteroids. Therefore, macrolides and steroids may be therapeutic potential for the treatment of airway hypersecretion in the inflamed airways.

越来越多的证据表明，一氧化氮(NO)在呼吸道合成和释放，从而在多种呼吸道功能中发挥作用。在本实验中，为了确定上皮源性NO是否参与调节氯的分泌，从而调节水向气道腔的分泌，我们研究了体外培养的人支气管上皮细胞。膜片钳研究表明，高钙溶液加缓激肽或NO供体S-硝基-N-青霉胺和硝普钠均可引起氯离子选择性电流和腔氯通道开放概率的增加。这种效应伴随着相应的非选择性电流的增加，通过使用非选择性电极的极谱测量，以及诱导性一氧化氮合酶(CNOS)样免疫反应的存在。另一方面，用大肠杆菌内毒素、白介素1β、肿瘤坏死因子α或干扰素γ刺激细胞，均可增加氯离子电导和单个氯离子通道电流。这种作用同样伴随着培养液中NO浓度的增加，但根据Northern分析和免疫细胞化学，iNOS mRNA和iNOS蛋白的表达被这些刺激上调。此外，14元大环内酯类化合物和糖皮质激素对这些作用有剂量依赖性的抑制作用。因此，大环内酯类和类固醇可能是治疗炎症呼吸道高分泌的潜在药物。