PO.MCB07.04 · 分子与细胞生物学
慢性电子烟气溶胶暴露使人肺上皮细胞中NF-κB信号失调并改变IRF依赖性天然免疫信号
Chronic e-cigarette aerosol exposure dysregulates NF-kB signaling and alters IRF-dependent innate immune signaling in human lung epithelial cells
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摘要 Abstract
中文摘要
背景：尽管电子烟被作为可燃烟草的更安全替代品进行推广，越来越多的证据表明长期使用可能损害呼吸系统健康。电子烟气溶胶含有有害成分，包括尼古丁、羰基化合物、金属、致癌物和活性氧（ROS）。过量的ROS可压垮抗氧化防御，驱动氧化应激和慢性炎症。NF-κB是炎症和抗病毒免疫的核心调控因子，但慢性暴露于电子烟气溶胶对其的调控仍未明确界定。目的：确定慢性暴露于电子烟气溶胶如何改变肺上皮细胞中的NF-κB信号及下游炎症和抗病毒通路。
方法：将正常人支气管上皮细胞（NuLi-1）暴露于由两种商用烟草风味电子烟产品生成的气溶胶提取物，每隔一天一次，持续2周。暴露递送约30 ng/ml的尼古丁，以模拟电子烟使用者血浆中观察到的中位水平。通过实时RT-qPCR测量NF-κB mRNA水平。通过Western blotting定量NF-κB、TLR3、TLR4、IRF1、IRF3和IRF7的蛋白表达。采用Student's t检验评估统计学显著性。
结果：慢性电子烟气溶胶暴露显著上调NF-κB mRNA和蛋白水平。慢性暴露于电子烟气溶胶后，TLR3、TLR4和IRF7蛋白也升高，表明应激和病原体感应通路被激活。相反，IRF1和IRF3蛋白表达显著降低，与关键抗病毒转录因子受到抑制一致。这一模式反映出一种炎症性转变，其特征是NF-κB激活同时伴随IRF依赖性天然免疫信号的损害。
结论：慢性电子烟气溶胶暴露在人肺上皮细胞中诱导一种失调的炎症表型，表现为NF-κB激活和IRF介导的抗病毒通路受抑制。这些发现提示，长期使用电子烟可能损害上皮天然免疫，并增加对呼吸道感染和炎症性疾病的易感性。
基金支持：NIH/NCI（R01CA242168，Queimado）；TSET HPRC（Ganapathy）；NHI/NIGMS（U54GM104938-140）。
查看英文原文 English abstract
Background: Although electronic cigarettes (e-cigarettes) are marketed as safer alternatives to combustible tobacco, accumulating evidence indicates that chronic use may impair respiratory health. E-cigarette aerosols contain harmful constituents, including nicotine, carbonyl compounds, metals, carcinogens, and reactive oxygen species (ROS). Excess ROS can overwhelm antioxidant defenses, driving oxidative stress and chronic inflammation. NF-κB is a central regulator of inflammation and antiviral immunity, yet its modulation by chronic exposure to e-cigarette aerosol remains poorly defined. Objective: To determine how chronic exposure to e-cigarette aerosols alters NF-κB signaling and downstream inflammatory and antiviral pathways in lung epithelial cells.
Methods: Normal human bronchial epithelial cells (NuLi-1) were exposed to aerosol extracts generated from two commercial tobacco-flavored e-cigarette products every other day for 2 weeks. Exposure delivered approximately 30 ng/ml of nicotine to mimic the median levels observed in the plasma of e-cigarette users. NF-κB mRNA levels were measured by real-time RT-qPCR. Protein expressions of NF-κB, TLR3, TLR4, IRF1, IRF3 and IRF7 were quantified by Western blotting. Statistical significance was evaluated by Student's t -test.
Results: Chronic e-cigarette aerosol exposure significantly upregulated NF-κB mRNA and protein levels. TLR3, TLR4, and IRF7 proteins were also elevated after chronic exposure to e-cigarette aerosols, indicating activation of stress- and pathogen-sensing pathways. In contrast, IRF1, and IRF3 protein expression were significantly decreased, consistent with suppression of key antiviral transcription factors. This pattern reflects an inflammatory shift characterized by NF-κB activation with concurrent impairment of IRF-dependent innate immune signaling.
Conclusion: Chronic e-cigarette aerosol exposure induces a dysregulated inflammatory phenotype in human lung epithelial cells, marked by NF-κB activation and suppression of IRF-mediated antiviral pathways. These findings suggest that chronic e-cigarette use may compromise epithelial innate immunity and increase susceptibility to respiratory infections and inflammatory disease.
Grant support: NIH/NCI (R01CA242168, Queimado); TSET HPRC (Ganapathy); NHI/NIGMS (U54GM104938-140).
利益披露 Disclosure
V. Ganapathy, None..
S. Thottungal Parambil, None..
J. Manyanga, None..
G. Chengizkhan, None..
M. Chinnaiyan, None..
A. Hammoudi, None..
B. Sadhasivam, None..
I. Ramachandran, None..
D. Rubenstein, None..
L. Queimado, None.