Long noncoding RNA HOXA-AS2 ameliorates chronic intermittent hypoxia-induced lung inflammation by regulating miR-17-5p/tipe2 axis

Kun Gao; Aiai Lv; Qiang Zhang; Yanzhong Li; Zhiyong Yue; Shuai Xu

doi:10.15586/aei.v51i2.701

Kun Gao

Department of Otorhinolaryngology Head and Neck Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.

Aiai Lv

Department of Internal Medicine, Public Health Clinical Center, Affiliated to Shandong University, Jinan, Shandong, China.

Qiang Zhang

Department of Otorhinolaryngology Head and Neck Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.

Yanzhong Li

Department of Otorhinolaryngology, Qilu Hospital of Shandong University, NHC Key Laboratory of Otorhinolaryngology (Shandong University), Jinan, Shandong, China.

Zhiyong Yue

Department of Otorhinolaryngology Head and Neck Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.

Shuai Xu

Department of Otorhinolaryngology Head and Neck Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.

Keywords

chronic intermittent hypoxia, HOXA-AS2, lung inflammation, miR-17-5p, tipe2

Abstract

Purpose: The purpose is to confirm whether long noncoding RNA HOXA-AS2 relieves chronic intermittent hypoxia (CIH)-induced lung inflammation.

Methods: Male Sprague Dawley rats were used to establisha CIH rat model. Hematoxylin and Eosin staining was used on the lung tissue injury to determine the successful construction of CIH animal model. Arterial partial pressure of oxygen (PaO₂) and carbon dioxide (PaCO₂) were measured. HOXA-AS2 was overexpressed to evaluate its role in the progression and development of CIH. T cell differentiation and cytokine production were determined using flow cytometry. Cell apoptosis was determined using terminal deoxynucleotidyl transferase dUTP nick end labelling assay kit. The target of HOXA-AS2 and miR-17-5p was predicted by the Encyclopedia of RNA Interactomes (ENCORI) and confirmed using luciferase assay.

Results: HOXA-AS2 was downregulated in CIH rat models. Lung tissue injury was observed in CIH rats, and the injury was attenuated by the overexpression of HOXA-AS2. PaO₂ was reduced and PaCO₂ was induced in CIH rats, which was reversed by the overexpression of HOXA-AS2. The overexpression of HOXA-AS2 inhibited CIH-induced cell apoptosis. It also reversed alterations in the levels of interferon gamma (IFNγ), interleukin (IL)-2, IL-6, IL-1β, tumor necrosis factor alpha (TNF-α), and transforming growth factor beta1 (TGF-β1) in rats caused by CIH. The overexpression of HOXA-AS2 prevented the induction in CD4⁺ IFN-γ⁺ T cells and reduction in CD4⁺TGF-β1⁺ T cells. The overexpression of HOXA-AS2 upregulated tumor necrosis factor-alpha-induced protein 8-like 2 (tipe2) key regulator through directly targeting miR-17-5p. Further experiments proved that tipe2 was the direct target of miR-17-5p.

Conclusion: This study manifested that HOXA-AS2 acted as an anti-inflammatory regulator and protected lung tissue injury from CIH in the rat model; this was mediated by upregulation of tipe2 through directly targeting miR-17-5p. HOXA-AS2 upregulated the expression of tipe2, providing new understanding and therapeutic target for CIH.

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