School of Health & Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia.
Br J Pharmacol. 2021 Apr;178(8):1805-1818. doi: 10.1111/bph.15400. Epub 2021 Feb 27.
It is well established that both smokers and patients with COPD are at a significantly heightened risk of cardiovascular disease (CVD), although the mechanisms underpinning the onset and progression of co-morbid CVD are largely unknown. Here, we explored whether cigarette smoke (CS) exposure impairs vascular function in mice and given the well-known pathological role for oxidative stress in COPD, whether the antioxidant compound ebselen prevents CS-induced vascular dysfunction in mice.
Male BALB/c mice were exposed to either room air (sham) or CS generated from nine cigarettes per day, 5 days a week for 8 weeks. Mice were treated with ebselen (10 mg·kg , oral gavage once daily) or vehicle (5% w/v CM cellulose in water) 1 h prior to the first CS exposure of the day. Upon killing, bronchoalveolar lavage fluid (BALF) was collected to assess pulmonary inflammation, and the thoracic aorta was excised to investigate vascular endothelial and smooth muscle dilator responses ex vivo.
CS exposure caused a significant increase in lung inflammation which was reduced by ebselen. CS also caused significant endothelial dysfunction in the thoracic aorta which was attributed to a down-regulation of eNOS expression and increased vascular oxidative stress. Ebselen abolished the aortic endothelial dysfunction seen in CS-exposed mice by reducing the oxidative burden and preserving eNOS expression.
Targeting CS-induced oxidative stress with ebselen may provide a novel means for treating the life-threatening pulmonary and cardiovascular manifestations associated with cigarette smoking and COPD.
众所周知，吸烟者和 COPD 患者患心血管疾病（CVD）的风险显著增加，尽管导致合并 CVD 发病和进展的机制在很大程度上尚不清楚。在这里，我们探讨了香烟烟雾（CS）暴露是否会损害小鼠的血管功能，并且鉴于氧化应激在 COPD 中的众所周知的病理作用，抗氧化化合物依布硒啉是否可以预防 CS 诱导的小鼠血管功能障碍。
雄性 BALB/c 小鼠暴露于空气（假）或每天 9 支香烟，每周 5 天，持续 8 周的 CS 中。在每天第一次 CS 暴露前 1 小时，用依布硒啉（10mg·kg，口服灌胃）或载体（5％w/v CM 纤维素在水中）处理小鼠。处死时，收集支气管肺泡灌洗液（BALF）以评估肺部炎症，并切除胸主动脉以研究血管内皮和平滑肌舒张反应。
CS 暴露导致肺炎症明显增加，依布硒啉可减轻肺炎症。CS 还导致胸主动脉明显的内皮功能障碍，这归因于 eNOS 表达下调和血管氧化应激增加。依布硒啉通过减轻氧化应激和维持 eNOS 表达来消除 CS 暴露小鼠的主动脉内皮功能障碍。
用依布硒啉靶向 CS 诱导的氧化应激可能为治疗与吸烟和 COPD 相关的危及生命的肺部和心血管表现提供一种新方法。
