Polyinosinic:polycytidylic acid induces protein kinase D-dependent disassembly of apical junctions and barrier dysfunction in airway epithelial cells.
Polyinosinic:polycytidylic acid induces protein kinase D-dependent disassembly of apical junctions and barrier dysfunction in airway epithelial cells.
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DOI：
10.1016/j.jaci.2011.08.035
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发表时间：
2011-12
期刊：
影响因子：
--
通讯作者：
Georas SN
中科院分区：
文献类型：
--
作者：
Rezaee F;Meednu N;Emo JA;Saatian B;Chapman TJ;Naydenov NG;De Benedetto A;Beck LA;Ivanov AI;Georas SN
上皮屏障的破坏可能是过敏原致敏和哮喘的危险因素。病毒性呼吸道感染与哮喘加重密切相关，但呼吸道病毒对气道上皮屏障功能的影响尚不清楚。许多病毒产生双链RNA，这可以导致气道炎症并启动抗病毒免疫反应。本文研究了合成的双链RNA多肌苷：多胞酸（polyI:C）对体外气道上皮屏障结构和功能的影响。16HBE14o-人支气管上皮细胞和原代气道上皮细胞在气液界面上生长，在Transwell插入物上汇合，并暴露于polyI:C。我们利用免疫荧光显微镜测量上皮间电阻、荧光标记物的胞外通量和上皮顶端连接的结构，研究上皮屏障功能。PolyI:C诱导上皮间电阻的显著降低和细胞旁通透性的增加。免疫荧光显微镜显示，occludens-1、occludin、E-cadherin、β-catenin的连接定位明显降低，连接相关的肌动蛋白丝组织紊乱。PolyI:C诱导蛋白激酶D （PKD）磷酸化，PKD拮抗剂减弱PolyI:C诱导的根尖连接解体和屏障功能障碍。PolyI:C对气道上皮屏障具有强大的、以前未被怀疑的破坏作用。PolyI: c依赖性屏障破坏是由上皮顶端连接的破坏介导的，这依赖于PKD信号。这些发现提示了病毒性呼吸道感染、气道炎症和过敏原致敏之间潜在的新机制。
Disruption of the epithelial barrier might be a risk factor for allergen sensitization and asthma. Viral respiratory tract infections are strongly associated with asthma exacerbation, but the effects of respiratory viruses on airway epithelial barrier function are not well understood. Many viruses generate double-stranded RNA, which can lead to airway inflammation and initiate an antiviral immune response. We investigated the effects of the synthetic double-stranded RNA polyinosinic:polycytidylic acid (polyI:C) on the structure and function of the airway epithelial barrier in vitro. 16HBE14o- human bronchial epithelial cells and primary airway epithelial cells at an air-liquid interface were grown to confluence on Transwell inserts and exposed to polyI:C. We studied epithelial barrier function by measuring transepithelial electrical resistance and paracellular flux of fluorescent markers and structure of epithelial apical junctions by means of immunofluorescence microscopy. PolyI:C induced a profound decrease in transepithelial electrical resistance and increase in paracellular permeability. Immunofluorescence microscopy revealed markedly reduced junctional localization of zonula occludens-1, occludin, E-cadherin, β-catenin, and disorganization of junction-associated actin filaments. PolyI:C induced protein kinase D (PKD) phosphorylation, and a PKD antagonist attenuated polyI:C-induced disassembly of apical junctions and barrier dysfunction. PolyI:C has a powerful and previously unsuspected disruptive effect on the airway epithelial barrier. PolyI:C-dependent barrier disruption is mediated by disassembly of epithelial apical junctions, which is dependent on PKD signaling. These findings suggest a new mechanism potentially underlying the associations between viral respiratory tract infections, airway inflammation, and allergen sensitization.
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