Centro Cardiologico Monzino, IRCCS, via Parea 4, Milan, Italy.
Cardiovasc Res. 2011 Jun 1;90(3):475-83. doi: 10.1093/cvr/cvr032. Epub 2011 Feb 1.
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.
Serum from nine healthy active smokers (AS) compared with serum from nine non-smokers (NS) showed higher levels of interleukin-1beta (IL-1β) and tumour necrosis factor-alpha (TNF-α) 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-1β and TNF-α(TS/IL-1β/TNF-α). In ECs increased ROS production and COX-2 mRNA induced by serum from AS correlated positively with their serum levels of IL-1β and TNF-α. Moreover, a positive correlation was observed between ROS generation and COX-2 mRNA. Simultaneous immuno-neutralization of IL-1β and TNF-α 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-1β/TNF-α. 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.
吸烟会引起炎症和内皮功能障碍，这些过程与动脉粥样硬化血栓形成疾病有关。我们假设，在吸烟者血液中的炎症细胞因子与香烟烟雾中的循环成分之间存在相互作用，这是诱导内皮细胞中活性氧（ROS）和环氧化酶-2（COX-2）产生所必需的。然后，我们探讨了这些作用涉及的分子机制。
与非吸烟者（NS）的血清相比，来自 9 名健康活跃吸烟者（AS）的血清显示出更高水平的白细胞介素-1β（IL-1β）和肿瘤坏死因子-α（TNF-α），并且具有更大的诱导 ROS 产生、p47phox 向质膜易位以及内皮细胞（EC）中 COX-2 mRNA 和蛋白表达的能力。在体内和体外用香烟烟雾水提取物加 IL-1β 和 TNF-α（TS/IL-1β/TNF-α）处理后也获得了类似的结果。AS 血清诱导的 EC 中 ROS 产生和 COX-2 mRNA 的增加与它们血清中 IL-1β 和 TNF-α 的水平呈正相关。此外，还观察到 ROS 生成与 COX-2 mRNA 之间存在正相关。同时免疫中和 AS 血清中的 IL-1β 和 TNF-α 可预防由 AS 血清引起的内皮功能障碍。NADPH 氧化酶抑制剂和/或 p47phox siRNA 减少了由 AS 血清或 TS/IL-1β/TNF-α介导的 ROS 产生和 COX-2 表达以及丝裂原活化蛋白激酶（p38MAPK）和 Akt 的磷酸化。最后，直接抑制 p38MAPK 和 Akt 活性也消除了由这两种类型的刺激介导的 COX-2 表达。我们的结果表明，炎症细胞因子与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。
