Ebselen reduces cigarette smoke-induced vascular endothelial dysfunction in mice

Abstract

Background and Purpose: 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 comorbid 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. Experimental Approach: Male BALB/c mice were exposed to either room air (sham) or CS generated from 9 cigarettes per day, 5 days a week for 8 weeks. Mice were treated with ebselen (10mg/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 sacrifice, 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. Key Results: 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 downregulation 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. Conclusion and Implications: 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.

Ebselen Prevents Cigarette Smoke-Induced Cognitive Dysfunction In Mice By Preserving Hippocampal Synaptophysin Expression

“…Smoking cessation restores body weight and reduces BALF cellularity Similar to previously reported, CS exposure caused a suppression of weight gain when compared to sham mice [7,32,33]. Upon cessation, the body weight of the mice rapidly re-bounced and were no different to that of sham-treated at 18 Cessation gradually alters the pulmonary in ammatory pro le.…”

“…The hippocampus is highly susceptible to oxidative insults [72], thus, it seems highly plausible that ebselen may be able to reduce the CS-induced oxidative burden globally, however, hippocampal oxidative stress may remain elevated alongside the elevated microglial pro le. This is not unprecedented given that the attenuation of pulmonary in ammation following ebselen administration is largely due to a reduction in neutrophilic in ltration [7,10], leading us to postulate that ebselen's memory enhancing ability may be exerted via a microglial-independent mechanism which targets synaptic integrity in smokers. Synapses are formed by the functional contact of presynaptic axonal terminals with postsynaptic dendritic processes allowing for the e cient transmission of signal [73,74].…”

“…At the end of the study, the lungs were lavaged in situ using phosphate buffered saline (PBS) as previously published [7,32,34]. BAL uid (BALF) cytospin slides were prepared and analyzed; identifying macrophages, neutrophils and lymphocytes using standard morphological criteria.…”

“…Noxious particles in CS damage the lung epithelium, driving the recruitment of macrophages, neutrophils, and lymphocytes as well as the release of pro-in ammatory mediators [2][3][4] and reactive oxygen species (ROS) [5,6] into the lungs, that drives persisting pulmonary in ammation. Pharmacotherapies targeting oxidative stress, such as the glutathione peroxidase (GPx) mimetic, ebselen, can ameliorate lung in ammation in murine models of COPD [7][8][9][10]. It is postulated that injuries of the lung epithelium permits the "spill-over" of pro-in ammatory and oxidative stress mediators into the systemic circulation, leading to secondary medical conditions elsewhere, also known as comorbidities [11].…”

Inhibition of oxidative stress by apocynin attenuated COPD progression and vascular injury by cigarette smoke exposure

“…Although yet to be fully established, the "spill-over" of local lung inflammation in COPD has been demonstrated to drive CVD risk (Barnes, 2019). In a preclinical model of COPD, Brassington et al (Brassington et al, 2021) demonstrated that oxidative stress from CS exposure may cause inflammatory cell infiltration into the vascular wall and endothelial dysfunction, suggesting oxidative stress may be a missing link. In addition to marking the imbalance between reactive oxygen species (ROS) and endogenous antioxidant defence, oxidative stress may simultaneously exacerbate comorbidities, stimulating fibrosis and emphysema development of the lungs by amplifying chronic inflammation (Barnes, 2020).…”