Abstract
AimsObstructive 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 MethodsThe effects of dexamethasone (Dex) were determined using the ovalbumin (OVA)-challenged mouse model of asthma and transforming growth factor (TGF)-β 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 FindingsUnder 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-κB 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-β combined with CIH and suppressed activation of the p38 MAPK pathway, oxidative stress injury, and NF-κB nuclear transcription (p < 0.05).SignificanceThese results indicated that CIH decreased GC sensitivity by activating the p38 MAPK signaling pathway.
Highlights
Asthma is a heterogeneous disease characterized by chronic airway inflammation (Boonpiyathad et al, 2019; Lambrecht et al, 2019; McGregor et al, 2019)
Chronic intermittent hypoxia exposure reduced the effects of Dex in the mouse model, which were ameliorated by the p38 MAPK inhibitor, SB239063
As compared to control mice, OVA sensitization and challenge provoked a significant increase in the number of macrophages, eosinophils, neutrophils, and lymphocytes in bronchoalveolar lavage fluid (BALF), and these increases were reversed after Dex administration (Figures 2B–E)
Summary
Asthma is a heterogeneous disease characterized by chronic airway inflammation (Boonpiyathad et al, 2019; Lambrecht et al, 2019; McGregor et al, 2019). Obstructive sleep apnea (OSA) is characterized by chronic intermittent hypoxia (CIH) and sleep fragmentation (Somers et al, 1995), resulting in injury to multiple systems and affecting the quality of life and survival of patients (Tsai, 2017). It is noteworthy that the coexistence of asthma and OSA is not a simple superposition of symptoms, but a synergistic effect (Julien et al, 2009; Broytman et al, 2015; Qiao and Xiao, 2015). The previous studies demonstrated that CIH led to bronchial hyperreactivity, increased airway and systemic inflammation, and promoted the risk of refractory asthma (Broytman et al, 2015). It has been found that patients with asthma and OSA are more likely to develop SR asthma which is difficult to treat (Prasad et al, 2020)
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