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

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.

Scopoletin inhibits PDGF-BB-induced proliferation and migration of airway smooth muscle cells by regulating NF-κκB signaling pathway

“…7 Schisandrin B could also attenuate airway inflammation by mediating the NF-κB pathway in asthma animal model. 17 These studies confirmed that this pathway could serve as a promising target for asthma.…”

“…NF-κB signaling plays an important role in regulating proinflammatory cytokines production, and recruiting eosinophils, which promotes allergic inflammation. 17 Activation of NF-κB pathway has been implicated in allergic asthma. To reveal the potential mechanism, the activation of NF-κB signaling pathway was analyzed (Figure 4).…”

Intermittent Hypoxia on the Attenuation of Induced Nasal Allergy and Allergic Asthma by MAPK Signaling Pathway Downregulation in a Mice Animal Model

“…Other authors demonstrated that chronic intermittent hypoxia (CIH) led to bronchial hyperreactivity, increased airway and systemic inflammation, and thus promoted the risk of refractory asthma [ 18 ]. In addition, according to the studies, treatment with p38 MAPK inhibitor substantially decreased the inflammation scores in an asthma mice model [ 8 ]. Also, CIH decreased the glucosteroid sensitivity by activating the p38 MAPK signaling pathway.…”

“…Additionally, ERK and JNK phosphorylation and activation also can be affected after stimulation with glucosteroids, although the mechanism of this regulation is not fully elucidated [ 19 ]. Other studies have shown that CIH exposure led to the activation of the p38 MAPK pathway in the nervous system and vascular endothelium [ 8 ]. From this point of view, our study also showed that IH induced ERK and p38 MAPK activation by phosphorylation, at the same time with no significant changes in JNK phosphorylation, even though the results show downregulation of MEK phosphorylation.…”

“…However, IH and its biological effects have not yet been fully understood. Whereas some research claims that IH contributes to pathologic medical conditions [ 4 , 5 , 6 ], other research focuses on its curative properties [ 4 , 5 , 7 , 8 ]. Repeated episodes of hypoxia interspersed with normoxic intervals are the key components of IH [ 5 ].…”