Investigating antioxidant therapy for steroid-resistant asthma

Abstract

Introduction: Steroid-resistant (SR) asthma represents a significant clinical and economic burden. The mechanisms which drive SR asthma are unknown, but respiratory infections have been implicated in the development of disease. Infections increase oxidative stress in the lung and SR asthma is associated with defective antioxidant responses and increased oxidative stress. Hypotheses: Respiratory infections induce changes in the asthmatic airway that increase oxidative stress and contribute to dysregulated antioxidant responses which play a crucial role in the development of SR asthma. Aim: To determine the effects of antioxidant therapy on oxidative stress, inflammation and airways hyper-responsiveness (AHR) in a murine model of Chlamydia -induced SR asthma. Methods: Oxidative stress was measured in our established model of Chlamydia -induced SR allergic airways disease (AAD) using 3-nitrotyrosine and 8-isoprostane assays. The effects of treatment with vitamin E or an NRF2 activator on oxidative stress, inflammation and AHR in SRAAD were assessed compared to dexamethasone (DEX). Results: We show that oxidative stress responses are increased in Chlamydia -induced SRAAD compared to controls with steroid-sensitive AAD. Oxidative stress responses in SRAAD are not affected by DEX. Vitamin E treatment alone reduces oxidative stress and, when combined with DEX, suppresses oxidative stress, inflammation and AHR, in SRAAD. Treatment with the NRF2 activator suppresses all features of SRAAD in the absence of DEX. Conclusions: SRAAD is associated with increased oxidative stress that are resistant to steroids. Our findings suggest that antioxidant therapy may be appropriate for SR asthma especially when combined with steroid therapy.