TLR2 and TLR4 Expression and Inflammatory Cytokines are Altered in the Airway Epithelium of Those with Alcohol Use Disorders
TLR2 and TLR4 Expression and Inflammatory Cytokines are Altered in the Airway Epithelium of Those with Alcohol Use Disorders
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DOI：
10.1111/acer.12803
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发表时间：
2015-09-01
影响因子：
3.2
通讯作者：
Burnham, Ellen L.
中科院分区：
文献类型：
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作者：
Bailey, Kristina L.;Romberger, Debra J.;Burnham, Ellen L.
背景肺具有高度调节的先天免疫系统，以保护自身免受吸入的微生物和毒素的侵害。第一道防线是粘膜纤毛清除，但如果入侵者克服了这一点，炎症途径就会被激活。Toll样受体（TLR）在气道上皮上表达。它们的信号传导启动炎性级联反应，并导致产生炎性细胞因子，如白细胞介素（IL）-6和IL-8。我们假设，气道上皮侮辱，包括大量饮酒或吸烟，会改变TLRs的气道epithelium.MethodsBronchoscopy支气管肺泡灌洗和刷的气道上皮细胞的表达，否则健康的受试者进行正常的胸片和肺功能测定。使用酒精使用障碍识别测试（AUDIT）确定酒精使用障碍（AUD）史，并获得吸烟史。所有组的年龄、性别和营养状况相似。采用实时荧光定量聚合酶链反应（PCR）检测TLR 1 ~ 9，酶联免疫法检测TNF-α、IL-6和IL-8。结果26例非吸烟/非AUD受试者、28例吸烟/非AUD受试者、36例吸烟/AUD受试者和17例非吸烟/AUD受试者的气道刷拭标本均采集自气道。我们发现，与不吸烟/非AUD受试者相比，TLR 2在AUD受试者中上调，并与他们的AUDIT评分相关。我们还测量了AUD受试者中TLR 4表达的减少，这与AUDIT评分相关。IL-6和IL-8也增加了在支气管冲洗从AUD subjects.ConclusionsWe以前在正常的人支气管上皮细胞，体外酒精暴露上调TLR 2通过NO/cGMP/PKG依赖的途径，导致革兰氏阳性菌产物刺激后的炎症细胞因子的产生上调。我们目前的翻译研究证实，TLR 2在患有AUDs的人类中也上调。
BackgroundThe lung has a highly regulated system of innate immunity to protect itself from inhaled microbes and toxins. The first line of defense is mucociliary clearance, but if invaders overcome this, inflammatory pathways are activated. Toll-like receptors (TLRs) are expressed on the airway epithelium. Their signaling initiates the inflammatory cascade and leads to production of inflammatory cytokines such as interleukin (IL)-6 and IL-8. We hypothesized that airway epithelial insults, including heavy alcohol intake or smoking, would alter the expression of TLRs on the airway epithelium.MethodsBronchoscopy with bronchoalveolar lavage and brushings of the airway epithelium was performed in otherwise healthy subjects who had normal chest radiographs and spirometry. A history of alcohol use disorders (AUDs) was ascertained using the Alcohol Use Disorders Identification Test (AUDIT), and a history of cigarette smoking was also obtained. Age, gender, and nutritional status in all groups were similar. We used real-time polymerase chain reaction (PCR) to quantitate TLR1 to 9 and enzyme-linked immune assay to measure tumor necrosis factor-, IL-6, and IL-8.ResultsAirway brushings were obtained from 26 nonsmoking/non-AUD subjects, 28 smoking/non-AUD subjects, 36 smoking/AUD subjects, and 17 nonsmoking/AUD subjects. We found that TLR2 is up-regulated in AUD subjects, compared to nonsmoking/non-AUD subjects, and correlated with their AUDIT scores. We also measured a decrease in TLR4 expression in AUD subjects that correlated with AUDIT score. IL-6 and IL-8 were also increased in bronchial washings from AUD subjects.ConclusionsWe have previously demonstrated in normal human bronchial epithelial cells that invitro alcohol exposure up-regulates TLR2 through a NO/cGMP/PKG-dependent pathway, resulting in up-regulation of inflammatory cytokine production after Gram-positive bacterial product stimulation. Our current translational study confirms that TLR2 is also up-regulated in humans with AUDs.