Abstract
Corticosteroid insensitivity is a key characteristic of patients with severe asthma and COPD. These individuals experience greater pulmonary oxidative stress and inflammation, which contribute to diminished lung function and frequent exacerbations despite the often and prolonged use of systemic, high dose corticosteroids. Reactive oxygen and nitrogen species (RONS) promote corticosteroid insensitivity by disrupting glucocorticoid receptor (GR) signaling, leading to the sustained activation of pro-inflammatory pathways in immune and airway structural cells. Studies in asthma and COPD models suggest that corticosteroids need a balanced redox environment to be effective and to reduce airway inflammation. In this review, we discuss how oxidative stress contributes to corticosteroid insensitivity and the importance of optimizing endogenous antioxidant responses to enhance corticosteroid sensitivity. Future studies should aim to identify how antioxidant-based therapies can complement corticosteroids to reduce the need for prolonged high dose regimens in patients with severe asthma and COPD.
Highlights
superoxide dismutase (SOD) are present in every mammalian cell, but lower expression levels and activity are observed in the lung lining fluids and airway epithelial cells of individuals with asthma and chronic obstructive pulmonary disease (COPD) compared to healthy controls [241,242]
Corticosteroids will likely remain the standard of care, as their unique ability to effectively reduce inflammation in immune cells and airway structural cells make them suitable for managing asthma and COPD
Optimal corticosteroid efficacy may be dependent upon maintaining low levels of oxidative stress [226], highlighting the need to develop strategies that can preserve homeostatic redox balance in patients receiving corticosteroids
Summary
Chronic airway inflammation is key for the development of structural and functional changes to the airway that restrict airflow and contribute to exacerbations in asthma and COPD [41]. The inflammatory milieu in the airway is complex, heterogenous, and possibly dynamic. This complexity and the broad anti-inflammatory properties of corticosteroids make their use appealing to manage symptoms and disease progression. Studies in asthma or COPD patient cohorts have identified different physiological and immunological responses that are thought to influence disease severity and corticosteroid sensitivity [42,43]
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