β-elemene alleviates airway stenosis via the ILK/Akt pathway modulated by MIR143HG sponging miR-1275

Abstract

Background We have previously found that β-elemene could inhibit the viability of airway granulation fibroblasts and prevent airway hyperplastic stenosis. This study aimed to elucidate the underlying mechanism and protective efficacy of β-elemene in vitro and in vivo. Methods Microarray and bioinformatic analysis were used to identify altered pathways related to cell viability in a β-elemene-treated primary cell model and to construct a β-elemene-altered ceRNA network modulating the target pathway. Loss of function and gain of function approaches were performed to examine the role of the ceRNA axis in β-elemene's regulation of the target pathway and cell viability. Additionally, in a β-elemene-treated rabbit model of airway stenosis, endoscopic and histological examinations were used to evaluate its therapeutic efficacy and further verify its mechanism of action. Results The hyperactive ILK/Akt pathway and dysregulated LncRNA-MIR143HG, which acted as a miR-1275 ceRNA to modulate ILK expression, were suppressed in β-elemene-treated airway granulation fibroblasts; β-elemene suppressed the ILK/Akt pathway via the MIR143HG/miR-1275/ILK axis. Additionally, the cell cycle and apoptotic phenotypes of granulation fibroblasts were altered, consistent with ILK/Akt pathway activity. In vivo application of β-elemene attenuated airway granulation hyperplasia and alleviated scar stricture, and histological detections suggested that β-elemene's effects on the MIR143HG/miR-1275/ILK axis and ILK/Akt pathway were in line with in vitro findings. Conclusions MIR143HG and ILK may act as ceRNA to sponge miR-1275. The MIR143HG/miR-1275/ILK axis mediates β-elemene-induced cell cycle arrest and apoptosis of airway granulation fibroblasts by modulating the ILK/Akt pathway, thereby inhibiting airway granulation proliferation and ultimately alleviating airway stenosis.

Differential expression of miRNAs revealed by small RNA sequencing in traumatic tracheal stenosis

“…Based on the aforementioned results, it was hypothesized that miRNAs are of importance to TTS occurrence and development, which concurs with those seen in other research studies. For instance, inhibiting the expression of miR-1275 has been reported to possibly alleviate airway stenosis ( ZHANG et al, 2021 ). Ye et al (2021 ) screened differentially expressed miRNAs in airway scars and normal airway mucosal tissues by gene chips.…”

“…They widely regulate life processes, including cell growth, proliferation, apoptosis, differentiation, and body metabolism ( Rupaimoole and Slack, 2017 ; Pu et al, 2019 ). Inhibiting the expression of miR-1275 has been reported to possibly alleviate airway stenosis ( ZHANG et al, 2021 ). Because of less research on miRNAs in TTS, this study aimed to investigate the influencing mechanism of miRNAs in the occurrence and development of TTS.…”

Construction and Comprehensive Analysis of the ceRNA Network to Reveal Key Genes for Benign Tracheal Stenosis

“…However, neutrophils also produce a large amount of oxygen free radicals, which can cause oxidative stress in wound tissue, delay the repair process and change the healing result ( Koh and DiPietro, 2011 ). It has been reported that after the operation on New Zealand rabbits, the tissue wound was accompanied by a large number of inflammatory cell infiltration such as neutrophils and macrophages ( Zhang et al, 2021 ).…”

“…Through co-expression network analysis and construction of ce-RNA network, a ce-RNA network of “lnc-RNA- miRNA-mRNA” composed of 8 lnc-RNAs, 31 mRNAs and 116 miRNAs, and a ce-RNA network of “circRNA- miRNA-mRNA” composed of 30 circRNAs, 36 mRNAs and 275 miRNAs were obtained. Some drugs have been found to inhibit cell cycle progression and promote the apoptosis of primary human airway granulation fibroblasts through Mir143Hg (LNCRNA)/Mir-1275 (Mirna)/ILK axis, thus effectively inhibiting the proliferation of airway granulation tissue and ultimately alleviating airway stenosis, which is a potential therapy for benign airway stenosis ( Zhang et al, 2021 ). This study can provide more theoretical support for similar regulatory pathways and therapeutic targets.…”

Distribution and chemotactic mechanism of CD4+ T cells in traumatic tracheal stenosis

“…Transforming growth factor (TGF)‐β is a key factor in fibrosis. Studies have revealed that a huge portion of TGF‐β accumulates locally in TS, causing excessive proliferation of fibroblasts, increased collagen synthesis, extracellular matrix deposition, and fibrosis through the action of TGF‐β/Smad2/3, ERK1/2, and other pathways, and eventually leading to airway stenosis 19–21 . Recent findings have also strongly suggested that TGF‐β is critical for developing and differentiating Forkhead box protein 3 (FoxP3) Tregs 22 .…”