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. 2021 Aug 27:12:703281.
doi: 10.3389/fphys.2021.703281. eCollection 2021.

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

Li Liang  1   2 , Xin Gu  3 , Hai Ji Shen  1 , Yu Heng Shi  1 , Yao Li  1 , Jie Zhang  1 , Yan Yan Chen  1 , Zhen He Chen  1 , Jia Yun Ma  1 , Qing Yun Li  4
Affiliations

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

Li Liang et al. Front Physiol. .

Abstract

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)-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 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-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).

Significance: These results indicated that CIH decreased GC sensitivity by activating the p38 MAPK signaling pathway.

Keywords: asthma; chronic intermittent hypoxia; glucosteroid; ovalbumin; p38 MAPK pathway.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Diagram of animal treatment.
FIGURE 2
FIGURE 2
Effects of dexamethasone (Dex) and the p38 MAPK inhibitor, SB239063, on the allergic asthma model with (chronic intermittent hypoxia) CIH exposure. (A) Airway hyperreactivity (AHR) was measured using an invasive pulmonary device for mice. (B) Macrophage cell count, (C) eosinophil cell count, (D) neutrophil cell count, and (E) lymphocyte cell count in bronchoalveolar lavage fluid (BALF). (F,G) Typical hematoxylin and eosin (H&E) staining images of the lung with quantification. (H) IL-4, (I) IL-5, and (J) IL-13 levels in BALF were detected by enzyme-linked immunosorbent assay (ELISA). (K) The level of CCL11 mRNA expression in the lungs as determined by Real-Time Quantitative Reverse Transcription-PCR (qRT-PCR). Data are shown as the mean ± SEM (n = 6; *p < 0.05; **p < 0.01; ***p < 0.001).
FIGURE 3
FIGURE 3
The p38 MAPK pathway regulated allergic asthma in mice with CIH exposure. (A,B) Representative images of phosphor-p38 (green) and DAPI (blue) immunofluorescence-stained lung sections and phosphor-p38 intensity. (C,D) Representative images of HO-1 (red) and DAPI (blue) immunofluorescence-stained lung sections and HO-1 intensity. (E,F) Representative images of p65 (green) and DAPI (blue) immunofluorescence-stained lung sections and p65 intensity. (G) Levels of phosphor-p38, MKP-1, HO-1, and nuclear p65 in the lung were detected by western blot. (H) Lung MDA concentration. (I) Lung GSH-Px activity. Data are shown as the means ± SEM (n = 6; *p < 0.05; **p < 0.01; ***p < 0.001).
FIGURE 4
FIGURE 4
Effects of Dex or the p38 MAPK inhibitor, SB239063, on airway smooth muscle cells (ASMCs). (A) ASMCs displayed the characteristic “hill and valley” appearance. Immunofluorescence staining indicated the expression of the contractile protein SM α-actin (Green). (B) Proliferation of ASMCs at 48 h was analyzed in the different groups. Cell proliferation following TGF-β (10 ng/ml) stimulation was determined by the MMT test. (C) The malondialdehyde (MDA) concentration in ASMCs was measured. (D) Activity of GSH-Px in ASMCs was measured. (E) The level of CCL11 mRNA expression in ASMCs was determined by qRT-PCR. (F) The levels of phosphor-p38, MKP-1, HO-1, and nuclear p65 protein in ASMCs were determined by western blotting. Data are shown as the mean ± SEM (n = 3; *p < 0.05; **p < 0.01; ***p < 0.001).
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