Abstract
BackgroundWe 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.MethodsMicroarray 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.ResultsThe 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.ConclusionsMIR143HG 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.
Highlights
We have previously found that β-elemene could inhibit the viability of airway granulation fibroblasts and prevent airway hyperplastic stenosis
Results β‐Elemene‐affected competing endogenous RNA (ceRNA) axis identified via microarray and bioinformatics analysis primary human airway granulation fibroblasts (PHAGF) was treated with β-elemene for 48 h, and the IC50 of β-elemene was 160 μg/ mL, which was calculated by the inhibition rate curve of cell proliferation determined by Cell counting kit-8 (CCK-8); it was used as the optimal intervention concentration of β-elemene in subsequent studies (Fig. 1a)
The screened suppressed mRNAs mapping to the focal adhesion pathway revealed that Integrin-linked kinase (ILK) and its downstream genes, the cell cycle related gene cyclin D1 and the anti-apoptosis gene B-cell lymphoma-2 (Bcl-2), were enriched in the ILK/Akt sub-pathway (Fig. 1f )
Summary
We have previously found that β-elemene could inhibit the viability of airway granulation fibroblasts and prevent airway hyperplastic stenosis. Benign airway stenosis is caused by non-malignant factors, including endotracheal intubation, tuberculosis, tracheotomy, systemic diseases, and tracheal anastomosis. This condition results in varying degrees of dyspnea or even death by asphyxia [1, 2]. The interventional therapeutic bronchoscopy will cause secondary damage to the airway structures, and granulation tissue hyperplasia and scarring during the wound healing will make the stenosis relapse. It may cause repeat bronchoscopy, resulting in a vicious cycle of "stenosis–intervention with impairment–restenosis after repair" [6]. Abnormal fibroblasts exhibit greater proliferation potential and resistance to apoptosis, worsening severe fibrosis responses
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
