Abstract
Renin-angiotensin system (RAS) is involved in TGF-β–mediated epithelial-to-mesenchymal transition (EMT) and is responsible for airway remodeling in refractory asthma. Obstructive sleep apnea (OSA), which affects RAS activity, is a risk factor for refractory asthma. We aimed to investigate how chronic intermittent hypoxia (IH), the main pathophysiology of OSA, exacerbates asthma and whether Ang-(1–7) protects against chronic IH–induced airway remodeling in asthma. We exposed ovalbumin (OVA)-challenged asthma mice to chronic IH and observed that chronic IH aggravated airway inflammation and collagen deposit in OVA-challenged mice. Compared with the OVA group, the OVA + chronic IH group had a lower expression level of epithelial marker E-cadherin and higher expression levels of mesenchymal markers α-smooth muscle actin and collagen IV in airway epithelia, accompanied with activation of TGF-β/Smad pathway. These changes were reversed by the administration of Ang-(1–7). Consistently, Ang-(1–7) mitigated chronic IH–induced activation of TGF-β–mediated EMT in lipopolysaccharide-treated bronchial epithelial cells in a dose-dependent manner, which was blocked by Ang-(1–7)–specific Mas receptor antagonist A779. Taken together, Ang-(1–7) rescued chronic IH–aggravated TGF-β–mediated EMT to suppress airway remodeling, implying that RAS activity is involved in the mechanisms of OSA-related airway dysfunction in asthma.
SIGNIFICANCE STATEMENT OSA is a risk factor for refractory asthma. In this study, we aimed to explore the mechanisms of how OSA exacerbates refractory asthma. We found that chronic IH induces TGF-β–mediated EMT and aggravates airway collagen deposit. We also found that Ang-(1–7) erased the aggravation of TGF-β–mediated EMT and epithelial fibrosis upon chronic IH exposure. These findings provided new insights that the ACE2/Ang-(1–7)/Mas axis might be considered as a potential therapeutic target for patients with asthma and OSA.
Footnotes
- Received June 5, 2020.
- Accepted August 25, 2020.
↵1 J.P.Z. and Y.N.L. contributed equally to this article as co-first authors.
We would like to acknowledge funding grants from the National Natural Science Foundation of China [81700085, 81700084], National Key R&D Program of China [2018YFC1311900], and Shanghai Key Discipline for Respiratory Disease [2017ZZ02014] and support from Innovative research team of high-level local universities in Shanghai.
All authors disclose no conflicts of interest.
- Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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