Wood Smoke Enhances Cigarette Smoke-Induced Inflammation by Inducing the Aryl Hydrocarbon Receptor Repressor in Airway Epithelial Cells
Wood Smoke Enhances Cigarette Smoke-Induced Inflammation by Inducing the Aryl Hydrocarbon Receptor Repressor in Airway Epithelial Cells
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DOI：
10.1165/rcmb.2014-0142oc
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发表时间：
2015-03-01
影响因子：
6.4
通讯作者：
Tesfaigzi, Yohannes
中科院分区：
文献类型：
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作者：
Awji, Elias G.;Chand, Hitendra;Tesfaigzi, Yohannes
我们之前的研究表明，暴露在木烟(WS)中的吸烟者患慢性支气管炎和肺功能下降的风险增加。本研究旨在确定WS引起不良反应的机制。我们用四组小鼠研究了WS暴露的影响。C57BL/6小鼠暴露于过滤空气中4周或12周，10 mg/m(3)WS暴露2 h/d，250 mg/m(3)香烟烟雾(CS)暴露6 h/d，或CS+WS(CW)暴露。过滤空气组和WS组没有炎症反应，但CW组的支气管肺泡灌洗液中中性粒细胞数量和中性粒细胞趋化因子角质形成细胞衍生趋化因子的水平是CS组的两倍。CW组小鼠肺泡灌洗液中的前列腺素E合成酶(PGE(2))、环氧合酶(COX)-2和微粒体前列腺素E合成酶(mPGES-1)的水平以及抗炎脂氧素A4的水平均较CS小鼠降低了三倍。我们在原代人类呼吸道上皮细胞中复制了在小鼠身上观察到的变化。免疫沉淀结果显示，WS通过增加AHR抑制因子(AHRR)的表达，阻断芳烃受体(AHR)与AHR核转运蛋白的相互作用，从而降低COX-2和mPGES-1的表达。总之，这些研究表明，暴露于低浓度WS通过诱导AHRR表达来抑制AHR、COX-2和mPGES-1的表达以及PGE2和脂氧素A4的水平，从而增强了CS诱导的炎症。因此，AHRR是治疗WS相关CS诱导的炎症加重的潜在靶点。
Our previous studies showed that cigarette smokers who are exposed to wood smoke (WS) are at an increased risk for chronic bronchitis and reduced lung function. The present study was undertaken to determine the mechanisms for WS-induced adverse effects. We studied the effect of WS exposure using four cohorts of mice. C57Bl/6 mice were exposed for 4 or 12 weeks to filtered air, to 10 mg/m(3) WS for 2 h/d, to 250 mg/m(3) cigarette smoke (CS) for 6 h/d, or to CS followed by WS(CW). Inflammation was absent in the filtered air and WS groups, but enhanced by twofold in the bronchoalveolar lavage of the CW compared with CS group as measured by neutrophil numbers and levels of the neutrophil chemoattractant, keratinocyte-derived chemokine. The levels of the anti-inflammatory lipoxin, lipoxin A4, were reduced by threefold along with cyclo-oxygenase (COX)-2 and microsomal prostaglandin E synthase (mPGES)-1 in airway epithelial cells and PGE(2) levels in the bronchoalveolar lavage of CW compared with CS mice. We replicated, in primary human airway epithelial cells, the changes observed in mice. Immunoprecipitations showed that WS blocked the interaction of aryl hydrocarbon receptor (AHR) with AHR nuclear transporter to reduce expression of COX-2 and mPGES-1 by increasing expression of AHR repressor (AHRR). Collectively, these studies show that exposure to low concentrations of WS enhanced CS-induced inflammation by inducing AHRR expression to suppress AHR, COX-2, and mPGES-1 expression, and levels of PGE2 and lipoxin A4. Therefore, AHRR is a potential therapeutic target for WS-associated exacerbations of CS-induced inflammation.