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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.

the journal of pharmacology and experimental therapeutics/the journal of pharmacology and experimental therapeutics

Angiotensin-(1–7) Rescues Chronic Intermittent Hypoxia-Aggravated Transforming Growth Factor-<i>β</i>–Mediated Airway Remodeling in Murine and Cellular Models of Asthma

Angiotensin-(1–7) Rescues Chronic Intermittent Hypoxia-Aggravated Transforming Growth Factor-β–Mediated Airway Remodeling in Murine and Cellular Models of Asthma