Asthma exacerbations and airway redox imbalance under type 2 inflammatory conditions

Abstract

Asthma is a chronic inflammatory airway disease characterized by bronchial hyperresponsiveness and reversibility. Despite considerable advances in asthma treatment based on our understanding of its pathophysiology, asthma exacerbations remain challenging. To reduce asthma exacerbations, it is essential to identify triggers, patients’ risk factors, and underlying mechanisms. While exposure to viruses and environmental stimuli are known common triggers for asthma exacerbations, the key factors involved in asthma exacerbations have been identified as type 2 inflammation. Type 2 inflammatory biomarkers have been demonstrated to be useful in predicting individuals at risk of exacerbations. Furthermore, recent clinical trials of targeted biological therapy, which blocks the type 2 pathway, have supported the critical role of type 2 inflammation in asthma exacerbations. Although the specific mechanisms linking type 2 inflammation to asthma exacerbations have not yet been fully elucidated, increasing evidence shows that reduction/oxidation (redox) imbalance likely plays an important role in this association. Under type 2 inflammatory conditions, human airway epithelial cells activate 15-lipoxygenase-1 in complex with phosphatidylethanolamine binding protein-1, leading to the generation of electrophilic hydroperoxyl-phospholipids. When the accumulation of reactive lipid peroxidation surpasses a specific glutathione-dependent activity, these electrophilic compounds are not neutralized, leading to programmed cell death, ferroptosis. Reduced glutathione levels, caused by type 2 inflammation, may impair its ability to neutralize reactive lipid peroxidation. The accumulation of lipid peroxidation with intracellular redox imbalance may contribute to asthma exacerbations in individuals with type 2 inflammation. Inhibiting the ferroptotic pathway holds promise as a therapeutic strategy to alleviate asthma exacerbations.