FOXJ1 Prevents Cilia Growth Inhibition by Cigarette Smoke in Human Airway Epithelium In Vitro
FOXJ1 Prevents Cilia Growth Inhibition by Cigarette Smoke in Human Airway Epithelium In Vitro
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DOI：
10.1165/rcmb.2013-0363oc
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发表时间：
2014-11-01
影响因子：
6.4
通讯作者：
Crystal, Ronald G.
中科院分区：
文献类型：
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作者：
Brekman, Angelika;Walters, Matthew S.;Crystal, Ronald G.
呼吸道上皮纤毛细胞在清除吸入的病原体和异物方面起着中心作用，纤毛长度和协调跳动对呼吸道清除非常重要。基于体内研究表明，健康吸烟者的呼吸道上皮纤毛比健康不吸烟者短，我们通过在无毒浓度的香烟烟雾提取物(CSE)存在的情况下，在气液界面(ALI)培养中评估正常人类呼吸道基底细胞分化，探讨了香烟烟雾对纤毛发生的抑制机制。对培养第28天的纤毛长度的测量表明，CSE暴露与纤毛较短(P<；0.05)，重现了体内观察到的吸烟对纤毛长度的影响。这种表型与CSE介导的与纤毛相关的转录调节、鞭毛内运输、纤毛运动、结构完整性和基底发育相关的基因的广泛抑制有关，但与对照基因或上皮屏障完整性无关。慢病毒介导的纤毛相关转录因子FOXJ1的过表达可部分逆转CSE抑制的纤毛相关基因的表达，从而阻止CSE对纤毛生长的抑制。总而言之，这些数据表明，香烟烟雾的成分对纤毛生长相关基因的广泛抑制负有责任，但通过转录因子FOXJ1刺激纤毛生成，尽管吸烟带来压力，纤毛长度仍有可能保持接近正常水平。
Airway epithelium ciliated cells play a central role in clearing the lung of inhaled pathogens and xenobiotics, and cilia length and coordinated beating are important for airway clearance. Based on in vivo studies showing that the airway epithelium of healthy smokers has shorter cilia than that of healthy nonsmokers, we investigated the mechanisms involved in cigarette smoke-mediated inhibition of ciliogenesis by assessing normal human airway basal cell differentiation in air-liquid interface (ALI) cultures in the presence of nontoxic concentrations of cigarette smoke extract (CSE). Measurements of cilia length from Day 28 ALI cultures demonstrated that CSE exposure was associated with shorter cilia (P < 0.05), reproducing the effect of cigarette smoking on cilia length observed in vivo. This phenotype correlated with a broad CSE-mediated suppression of genes involved in cilia-related transcriptional regulation, intraflagellar transport, cilia motility, structural integrity, and basal body development but not of control genes or epithelial barrier integrity. The CSE-mediated inhibition of cilia growth could be prevented by lentivirus-mediated overexpression of FOXJ1, the major cilia-related transcription factor, which led to partial reversal of expression of cilia-related genes suppressed by CSE. Together, the data suggest that components of cigarette smoke are responsible for a broad suppression of genes involved in cilia growth, but, by stimulating ciliogenesis with the transcription factor FOXJ1, it may be possible to maintain close to normal cilia length despite the stress of cigarette smoking.