Data_Sheet_2_Chronic Intermittent Hypoxia Reduces the Effects of Glucosteroid in Asthma via Activating the p38 MAPK Signaling Pathway.ZIP

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.

【研究目的】阻塞性睡眠呼吸暂停（Obstructive sleep apnea, OSA）是糖皮质激素抵抗性（steroid-resistant, SR）哮喘的危险因素，但其潜在发病机制尚未明确。本研究旨在探讨阻塞性睡眠呼吸暂停的核心病理生理过程——慢性间歇性缺氧（chronic intermittent hypoxia, CIH）如何影响糖皮质激素（glucocorticoids, GCs）对哮喘的干预效果。
【主要方法】本研究采用卵清蛋白（ovalbumin, OVA）致敏激发的哮喘小鼠模型，以及转化生长因子-β（transforming growth factor-β, TGF-β）处理的气道平滑肌细胞（airway smooth muscle cells, ASMCs），设置伴或不伴CIH暴露的实验组，检测地塞米松（dexamethasone, Dex）的药理学效应。随后，在经p38丝裂原活化蛋白激酶（p38 MAPK）抑制剂SB239063处理的小鼠（n=6）与ASMCs模型（n=6）中，检测p38 MAPK信号通路的活化水平。
【主要发现】相较于单纯OVA致敏激发小鼠，OVA致敏激发联合CIH暴露小鼠的肺通气阻力值、支气管肺泡灌洗液（bronchoalveolar lavage fluid, BALF）中炎症细胞计数及炎症病理评分均显著升高（p < 0.05）。相较于OVA+地塞米松组，OVA+CIH+地塞米松组的上述指标同样显著升高（P < 0.05）。CIH暴露可增强肺组织与ASMCs中p38 MAPK通路的活化、氧化应激损伤程度及核因子κB（nuclear factor-κB, NF-κB）的表达水平，而地塞米松与SB239063处理可逆转上述异常变化。体外实验结果显示，地塞米松与SB239063可抑制TGF-β联合CIH诱导的ASMCs增殖，并下调p38 MAPK通路活化、氧化应激损伤及核因子κB的核转录水平（p < 0.05）。
【研究意义】本研究结果表明，CIH可通过激活p38 MAPK信号通路降低哮喘患者对GCs的治疗敏感性。