Cytokines present in smokers' serum interact with smoke components to enhance endothelial dysfunction
Cytokines present in smokers' serum interact with smoke components to enhance endothelial dysfunction
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DOI：
10.1093/cvr/cvr032
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发表时间：
2011-06-01
影响因子：
10.8
通讯作者：
Tremoli, Elena
中科院分区：
文献类型：
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作者：
Barbieri, Silvia S.;Zacchi, Elena;Tremoli, Elena
吸烟引起炎症和内皮功能障碍，这些过程与动脉粥样硬化性血栓形成疾病有关。我们假设吸烟者血液中的炎性细胞因子与香烟烟雾的循环成分之间的相互作用是诱导内皮细胞中活性氧（ROS）和环氧合酶-2（考克斯-2）的必要条件。然后，我们探讨了这些影响的分子机制。方法和结果与9名非吸烟者（NS）的血清相比，9名健康的主动吸烟者（AS）的血清显示更高水平的白细胞介素-1 β（IL-1 β）和肿瘤坏死因子-α（TNF-α）和更大的能力，诱导ROS的产生，p47 phox易位到质膜，和考克斯-2的mRNA和蛋白质表达在内皮细胞（EC）。用香烟烟雾的水提取物加IL-1 β和TNF-α（TS/IL-1 β/TNF-α）处理后，在体内和体外获得了类似的结果。AS血清诱导EC产生ROS和考克斯-2 mRNA的增加与其血清IL-1 β和TNF-α水平呈正相关。此外，ROS的产生与考克斯-2 mRNA的表达呈正相关。同时免疫中和IL-1 β和TNF-α可预防AS血清诱导的内皮功能障碍。NADPH氧化酶和/或p47 phox siRNA抑制剂减少ROS产生和考克斯-2表达以及AS血清或TS/IL-1 β/TNF-α介导的p38丝裂原活化蛋白激酶（p38 MAPK）和Akt的磷酸化。最后，直接抑制p38 MAPK和Akt的活性也消除了由两种类型的刺激介导的考克斯-2的表达。我们的研究结果表明，炎症细胞因子和烟草烟雾之间的相互作用在诱导内皮功能障碍中起着至关重要的作用。
Aims Cigarette smoking engenders inflammation and endothelial dysfunction, processes implicated in atherothrombotic disease. We hypothesized that an interaction between inflammatory cytokines in smokers' blood and circulating components of cigarette smoke is necessary to induce reactive oxygen species (ROS) and cyclooxygenase-2 (COX-2) in endothelium. We then explored the molecular mechanisms involved in these effects. Methods and results Serum from nine healthy active smokers (AS) compared with serum from nine non-smokers (NS) showed higher levels of interleukin-1beta (IL-1 beta) and tumour necrosis factor-alpha (TNF-alpha) and a greater ability to induce ROS production, p47phox translocation to the plasma membrane, and COX-2 mRNA and protein expression in endothelial cells (ECs). Similar results were obtained in vivo and in vitro after treatment with aqueous extracts of cigarette smoke plus IL-1 beta and TNF-alpha(TS/IL-1 beta/TNF-alpha). In ECs increased ROS production and COX-2 mRNA induced by serum from AS correlated positively with their serum levels of IL-1 beta and TNF-alpha. Moreover, a positive correlation was observed between ROS generation and COX-2 mRNA. Simultaneous immuno-neutralization of IL-1 beta and TNF-alpha prevented endothelial dysfunction induced by serum from AS. Inhibitors of NADPH oxidase and/or p47phox siRNA diminished ROS production and COX-2 expression as well as phosphorylation of p38 mitogen-activated protein kinase (p38MAPK) and Akt mediated either by AS serum or by TS/IL-1 beta/TNF-alpha. Finally, direct inhibition of p38MAPK and Akt activity also abolished COX-2 expression mediated by both types of stimuli. Our results suggest a crucial role played by interactions between inflammatory cytokines and tobacco smoke in the induction of endothelial dysfunction.