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首页> 外文期刊>BMC Neuroscience >Effect of full flavor and denicotinized cigarettes exposure on the brain microvascular endothelium: a microarray-based gene expression study using a human immortalized BBB endothelial cell line
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Effect of full flavor and denicotinized cigarettes exposure on the brain microvascular endothelium: a microarray-based gene expression study using a human immortalized BBB endothelial cell line

机译：全味和去烟味香烟暴露对大脑微血管内皮的影响：使用人类永生化BBB内皮细胞系的基于微阵列的基因表达研究

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Background Tobacco smoke (TS) toxicity to the brain microvasculature is still an understudied area till date. NF-E2 related factor (Nrf2) is a key transcription factor responsible for activating the antioxidant response element (ARE) genes following an oxidative insult. Till date, several studies targeting the blood brain barrier (BBB) have shown some protective role of Nrf2 in ischemia–reperfusion (IR) injury, however, its functional role in chronic smokers subjected to a life-long oxidative stress has never been addressed. This is of crucial importance since smokers have a much higher risk for cerebrovascular stroke and tobacco smoke exposure has been clearly shown to enhance BBB damage following an ischemia/reperfusion injury. Thus, the goal of our study was to investigate the defense pathways activated at the BBB endothelial level by TS exposure. Specifically we focused on Nrf2 and nuclear factor kappa-light-chain-enhancer of activated B signaling response (NF-κβ) as the central protective mechanisms related to oxidative insult. Results With the exception of Nicotine, both full flavor (3R4F) and decotinized (ULN) cigarettes activated Nrf2 and NFκβ pathways in hCMEC/D3 endothelial cells. Several detoxification and anti-oxidant genes including downstream products were also activated including NAD(P)H dehydrogenase quinone 1 (NQO-1), heme oxygenase-1 (HMOX-1), catalytic and modifier subunits of glutamate-cysteine ligase (GCL), solute carrier-SLC7A11). Gene expression levels of cytochrome P450s (CYP2S1 and CYP51A1) and efflux transporters P-glycoprotein (P-gp) and multi-drug resistance protein-4 (MRP4) were also enhanced. Increase of P-gp functional activity and depletion of GSH were also observed. Strikingly, toxicity of denicotinized (“reduced exposure”) cigarettes was equivalent to 3R4F (or worse). Conclusions This study provides a detailed analysis of Nrf2-related cytoprotective mechanisms activated in response to 3R4F and ULN-derived TS exposure correlating the results with their oxidative and inflammatory potential. Toxicants present in soluble cigarette smoke extracts (CSE) and not nicotine seem to be the primary determinant of vascular toxicity. In this respect our results from this and previous studies suggest that chronic TS exposure can overcome Nrf2 and NFκB-p65 dependent cytoprotective mechanisms of the brain microvascular endothelium possibly leading to BBB impairment and loss of BBB integrity.
机译：背景技术迄今为止，吸烟对大脑微脉管系统的毒性仍未被充分研究。 NF-E2相关因子（Nrf2）是关键转录因子，负责在氧化损伤后激活抗氧化反应元件（ARE）基因。迄今为止，针对血脑屏障（BBB）的多项研究表明Nrf2在缺血再灌注（IR）损伤中具有一定的保护作用，然而，其在终生吸烟者终生遭受氧化应激的功能中的作用从未得到解决。这一点至关重要，因为吸烟者脑血管中风的风险高得多，而且吸烟已清楚显示出吸烟会增加缺血/再灌注损伤后的血脑屏障损害。因此，我们研究的目的是研究TS暴露在BBB内皮水平激活的防御途径。具体来说，我们集中于Nrf2和活化的B信号反应（NF-κβ）的核因子κ轻链增强子作为与氧化损伤相关的中央保护机制。结果除尼古丁外，全味（3R4F）和无烟香烟都激活hCMEC / D3内皮细胞中的Nrf2和NFκβ途径。还激活了包括下游产物在内的一些排毒和抗氧化基因，包括NAD（P）H脱氢酶醌1（NQO-1），血红素加氧酶-1（HMOX-1），谷氨酸半胱氨酸连接酶（GCL）的催化和修饰亚基，溶质载体-SLC7A11）。细胞色素P450s（CYP2S1和CYP51A1）和外排转运蛋白P-糖蛋白（P-gp）和多药耐药蛋白4（MRP4）的基因表达水平也得到提高。还观察到P-gp功能活性的增加和GSH的消耗。令人惊讶的是，去烟味化（“减少接触”）的卷烟的毒性相当于3R4F（或更糟）。结论这项研究详细分析了响应3R4F和ULN衍生的TS暴露而激活的Nrf2相关的细胞保护机制，并将其结果与它们的氧化和炎性潜能相关。可溶性香烟烟雾提取物（CSE）中存在的毒素而不是尼古丁似乎是血管毒性的主要决定因素。在这方面，我们从本研究和以前的研究中得出的结果表明，长期TS暴露可以克服脑微血管内皮的Nrf2和NFκB-p65依赖性细胞保护机制，可能导致BBB损伤和BBB完整性丧失。

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