The nitroxide/antioxidant 3-carbamoyl proxyl attenuates disease severity in murine models of severe asthma

Abstract

Asthma is characterized by airway inflammation, hyper-responsiveness, symptoms of dyspnea, wheezing and coughing. In most patients, asthma is well controlled using inhaled corticosteroids and bronchodilators. A minority of patients with asthma develop severe disease, which is frequently only partially responsive or even resistant to treatment with corticosteroids. Severe refractory asthma is associated with structural changes in the airways, termed “airway remodeling”, and/or with neutrophilic rather than eosinophilic airway inflammation. While oxidative stress plays an important role in the pathophysiology of asthma, cyclic nitroxide stable radicals, which are unique and efficient catalytic antioxidants, effectively protect against oxidative injury. We have demonstrated that the nitroxide 3-carbamoyl proxyl (3-CP) attenuates airway inflammation and hyperresponsiveness in allergic asthma as well as bleomycin-induced fibrosis both using murine models, most probably through modulation of oxidative stress. The present study evaluates the effect of 3-CP on airway inflammation and remodeling using two murine models of severe asthma where mice are sensitized and challenged either by ovalbumin (OVA) or by house dust mite (HDM). 3-CP was orally administered during the entire period of the experiment or during the challenge period alone where its effect was compared to that of dexamethasone. The induced increase by OVA and by HDM of BALf cell counts, airway hyperresponsiveness, fibrosis, transforming growth factor-beta (TGF-β) levels in BALf and protein nitration levels of the lung tissue was significantly reduced by 3-CP. The effect of 3-CP, using two different murine models of severe asthma, is associated at least partially with attenuation of oxidative stress and with TGF-β expression in the lungs. The results of this study suggest a potential use of 3-CP as a novel therapeutic agent in different forms of severe asthma.