Ebselen abolishes vascular dysfunction in influenza A virus-induced exacerbations of cigarette smoke-induced lung inflammation in mice

Abstract

People with COPD are susceptible to respiratory infections which exacerbate pulmonary and/or cardiovascular complications, increasing their likelihood of death. The mechanisms driving these complications remain unknown but increased oxidative stress has been implicated. Here we investigated whether influenza A virus (IAV) infection, following chronic cigarette smoke (CS) exposure, worsens vascular function and if so, whether the antioxidant ebselen alleviates this vascular dysfunction. Male BALB/c mice were exposed to either room air or CS for 8 weeks followed by inoculation with IAV (Mem71, 1 x 104.5 pfu)). Mice were treated with ebselen (10 mg/kg) or vehicle (5% w/v CM-cellulose in water) daily. Mice were culled 3- and 10-days post-infection, and their lungs lavaged to assess inflammation. The thoracic aorta was excised to investigate endothelial and smooth muscle dilator responses, expression of key vasodilatory and oxidative stress modulators, infiltrating immune cells and vascular remodeling. CS increased lung inflammation and caused significant vascular endothelial dysfunction, which was worsened by IAV infection. CS-driven increases in vascular oxidative stress, aortic wall remodelling and supression of eNOS were not affected by IAV infection. CS and IAV infection significantly enhanced T-cell recruitment into the aortic wall. Ebselen abolished the exaggerated lung inflammation, vascular dysfunction and increased T-cell infiltration in CS and IAV-infected mice. Our findings showed that ebselen treatment abolished vascular dysfunction in IAV-induced exacerbations of cigarette smoke-induced lung inflammation indicating it may have potential for the treatment of cardiovascular comorbidities seen in acute exacerbations of COPD.

Ebselen Inhibits the Growth of Lung Cancer Cells via Cell Cycle Arrest and Cell Death Accompanied by Glutathione Depletion

“…Ebselen has received attention due to its prospect as a therapeutic drug for various diseases [ 13 , 16 , 23 , 24 , 25 ]. Furthermore, Ebselen has demonstrated its protective efficacy against bleomycin-induced lung fibrosis [ 26 ] and has restored vascular function during influenza A virus-induced exacerbations of cigarette smoke-induced lung inflammation [ 27 ].…”

Inhibition of oxidative stress by apocynin attenuated chronic obstructive pulmonary disease progression and vascular injury by cigarette smoke exposure

“…After washing, the sections were coverslipped using Fluoromount‐G™ mounting medium containing DAPI (Thermofisher Scientific, NY, USA), imaged on an Olympus Slide Scanner (VS120‐S5, Olympus Corporation, Tokyo, Japan) and analysed using Olympus cellSens Dimension™ desktop software (version 1:18, Olympus Corporation, Tokyo, Japan). Positive signals (n = 8 per group) are expressed as fluorescence intensity fold change or area of positive stain as previously described (Brassington et al, 2021 , 2022 ; Chan et al, 2020 , 2021 ). All analysis was completed in a blinded manner.…”

“…Positive signals (n = 8 per group) are expressed as fluorescence intensity fold change or area of positive stain as previously described (Brassington et al, 2021(Brassington et al, , 2022Chan et al, 2020Chan et al, , 2021. All analysis was completed in a blinded manner.…”

“…The tissues were paraffin embedded using HistoCore Arcadia (Leica Biosystems, MA, USA), serial cross sections were cut using a microtome (Leica Biosystems, MA, USA) at 4 μm thickness onto Superfrost ® Plus microscope slides (Thermofisher Scientific, NY, USA). The sections were dewaxed and rehydrated as previously described (Brassington et al, 2021(Brassington et al, , 2022, before antigen retrieval in sodium citrate buffer (10 mM Sodium Citrate, 0.05% Tween 20 at pH 6.0), blocking and permeabilization (PBS containing 1% bovine serum albumin, 22.52 mgÁml À1 glycine and 0.25% Triton X-100) as described on https://www.abcam.com/protocols/ immunocytochemistry-immunofluorescence-protocol.…”

Overview of the Mechanisms of Oxidative Stress: Impact in Inflammation of the Airway Diseases

“…Glutathione peroxidase (GPxs) is an important enzyme, belonging to the oxidoreductase family, containing selenium that protects cells from damage caused by lipid peroxide and H 2 O 2 [ 233 ]. In subjects with asthma and COPD, GPx activity is significantly reduced, and this is related both to the FEV1 values and to the body mass index of these subjects [ 234 ]. An example of antioxidant that exploits this mechanism is Ebselen [ 235 ], an organic selenium compound that acts as a GPx mimetic, effective in reducing inflammation and the release of inflammatory cytokines in the lungs of mice exposed to cigarette smoke.…”