Chronic Intermittent Hypoxia Reduces the Effects of Glucosteroid in Asthma via Activating the p38 MAPK Signaling Pathway

Aims Obstructive sleep apnea (OSA) is a risk factor for steroid-resistant (SR) asthma. However, the underlying mechanism is not well defined. This study aimed to investigate how chronic intermittent hypoxia (CIH), the main pathophysiology of OSA, influenced the effects of glucocorticoids (GCs) on asthma. Main Methods The effects of dexamethasone (Dex) were determined using the ovalbumin (OVA)-challenged mouse model of asthma and transforming growth factor (TGF)-beta treated airway smooth muscle cells (ASMCs), with or without CIH. The p38 MAPK signaling pathway activity was then detected in the mouse (n = 6) and ASMCs models (n = 6), which were both treated with the p38 MAPK inhibitor SB239063. Key Findings Under CIH, mouse pulmonary resistance value, inflammatory cells in bronchoalveolar lavage fluid (BALF), and inflammation scores increased in OVA-challenged combined with CIH exposure mice compared with OVA-challenged mice (p < 0.05). These indicators were similarly raised in the OVA + CIH + Dex group compared with the OVA + Dex group (P < 0.05). CIH exposure enhanced the activation of the p38 MAPK pathway, oxidative stress injury, and the expression of NF-kappa B both in lung tissue and ASMCs, which were reversed by treatment with Dex and SB239063. In the in vitro study, treatment with Dex and SB239063 decreased ASMCs proliferation induced by TGF-beta combined with CIH and suppressed activation of the p38 MAPK pathway, oxidative stress injury, and NF-kappa B nuclear transcription (p < 0.05). Significance These results indicated that CIH decreased GC sensitivity by activating the p38 MAPK signaling pathway.

Automated summary

The study showed that chronic intermittent hypoxia (CIH) reduced glucocorticoid sensitivity by activating the p38 MAPK signaling pathway. Results demonstrated that CIH exposure increased pulmonary resistance, inflammatory cell counts, and inflammation levels in OVA-challenged mice, indicating a worsening effect on asthma when combined with CIH.