Corticosteroid insensitivity in asthma associated with obstructive sleep apnoea: Role of oxidative stress and histone acetylation

Background and Purpose Obstructive sleep apnoea (OSA) worsens asthma control. Oxygen desaturation increases oxidative stress, contributing to corticosteroid insensitivity, a hallmark of severe asthma. This study investigated the impact of hypoxaemia and reactive oxygen species on corticosteroid responsiveness in asthma with OSA. Experimental Approach Asthmatic patients with apnoea–hypopnoea index (AHI) ≥ 5 h −1 were classified as OSA. Interleukin (IL)‐8 and IL‐6 production by peripheral blood mononuclear cells (PBMCs), serum cytokines, oxidative stress markers and nuclear histone deacetylase 2 (HDAC2) were quantified by enzyme‐linked immunosorbent assay. HDAC2 and hypoxia‐inducible factor‐1α (HIF‐1α) expression were evaluated by Western blotting and flow cytometry. Key Results Compared with non‐OSA asthmatics, OSA patients used higher inhaled corticosteroid doses and had increased serum thiobarbituric acid‐reactive substances and 8‐hydroxy‐2‐deoxyguanosine, but lower superoxide dismutase and total antioxidant capacity. HDAC2 was lower in OSA PBMCs and in non‐OSA PBMCs exposed to 5% O₂ than in normoxia. HDAC2 was correlated inversely with AHI, corticosteroid dose, serum IL‐8, oxidative stress, baseline production of IL‐8/IL‐6 and dexamethasone‐induced IL‐8 suppression. Dexamethasone inhibited TNF‐α‐induced IL‐8 and lipopolysaccharide (LPS)‐induced IL‐6 in non‐OSA PBMCs, but not in OSA PBMCs. HDAC2 inhibitor CAY10683 impaired corticosteroid action, while N‐acetylcysteine and inhibitors of HIF‐1α (CAY10585) or phosphoinositide 3‐kinase (LY294002) restored HDAC2 and corticosteroid sensitivity. Conclusions and Implications OSA is associated with oxidative stress, reduced HDAC2, and corticosteroid insensitivity in asthma. Antioxidants may help restore corticosteroid efficacy.