LncRNA IGF2-AS serves as a miR-106b-5p sponge to induce apoptosis and inflammatory reaction of bronchial epithelial cells in COPD.

The clinical characteristics of the three groups are listed in Table  1 . The age of the control group was from 55 to 82 years old (66.04 ± 6.00 years) and the BMI was 23.08 ± 2.49 kg/m 2 . The control group includes 50 males and 40 females and includes 49 current smokers. The stable COPD group was from 54 to 89 years old (67.90 ± 7.19 years) and included 51 males and 39 females. The AECOPD group was from 49 to 87 years old (66.81 ± 6.52 years) and included 54 males and 36 females. The three groups are comparable based on age, sex, BMI, and current smoker numbers and have no statistical difference. The values of FEV1 predicted, FEV1/FVC, and PEF were lower in the patients with COPD, especially in the AECOPD groups, compared with the control group. More cases in the AECOPD were in GOLD stages 2 and 3 in contrast to the stable COPD groups. Table 1 Clinical characteristics of the study groups Control Stable COPD AECOPD P -value n  = 90 n  = 90 n  = 90 Age (years) 66.04 ± 6.00 67.90 ± 7.19 66.81 ± 6.52 0.17 Sex (male/female) 50/40 51/39 54/36 0.82 BMI (kg/m 2 ) 23.08 ± 2.49 23.42 ± 2.03 23.59 ± 2.07 0.29 Current smoker (yes/no) 49/41 53/37 55/35 0.65 FEV1 predicted (%) 92.60 ± 6.00 60.12 ± 3.61 54.13 ± 3.99 < 0.001 FEV1/FVC (%) 84.60 ± 5.16 58.93 ± 3.86 53.27 ± 3.57 < 0.001 PEF(L/sec) 8.04 ± 1.07 5.48 ± 0.75 3.77 ± 0.55 < 0.001 GOLD stage 0.009 1 - 47 26 2 - 29 36 3 - 13 25 4 - 1 3 BMI body mass index, FEV1  forced expiratory volume in one second, PEF  peak expiratory flow, COPD  Chronic obstructive pulmonary disease,  AECOPD acute exacerbation of COPD Clinical characteristics of the study groups BMI body mass index, FEV1  forced expiratory volume in one second, PEF  peak expiratory flow, COPD  Chronic obstructive pulmonary disease,  AECOPD acute exacerbation of COPD RT-qPCR analysis indicated that IGF2-AS expression was elevated in patients with COPD, especially in patients with AECOPD, compared to the control group (Fig.  1 A). The disease severity of COPD patients was evaluated by the GOLD stage. The expression of IGF2-AS in different GOLD stages was further analyzed in stable COPD and AECOPD groups. Serum IGF2-AS showed higher levels at advanced GOLD stages in both stable COPD patients (Fig.  1 B) and AECOPD patients (Fig.  1 C). Fig. 1 Expression and clinical value of IGF2-AS in COPD with diagnosis and severity. A  Serum IGF2-AS expression was elevated in COPD patients, especially in patients with AECOPD. B  IGF2-AS expression in stable COPD patients with different GOLD stages. C  IGF2-AS levels in AECOPD patients with different GOLD stages. D  ROC curve was constructed to evaluate high IGF2-AS expression in differentiating stable COPD patients from healthy control.  E  ROC curve of IGF2-AS in distinguishing AECOPD from stable COPD patients. ns, no significance, * P  < 0.05, ** P  < 0.01, *** P  < 0.001 Expression and clinical value of IGF2-AS in COPD with diagnosis and severity. A  Serum IGF2-AS expression was elevated in COPD patients, especially in patients with AECOPD. B  IGF2-AS expression in stable COPD patients with different GOLD stages. C  IGF2-AS levels in AECOPD patients with different GOLD stages. D  ROC curve was constructed to evaluate high IGF2-AS expression in differentiating stable COPD patients from healthy control.  E  ROC curve of IGF2-AS in distinguishing AECOPD from stable COPD patients. ns, no significance, * P  < 0.05, ** P  < 0.01, *** P  < 0.001 The ROC curve was plotted to evaluate the diagnostic significance of IGF2-AS in COPD. As shown in Fig.  1 D, high expression of IFG2-AS in patients with stable COPD had a relatively high AUC value (0.884) with a cut-off value of 1.155 in distinguishing stable COPD patients from healthy control with a sensitivity of 82.22% and specificity of 84.44% (95%CI: 0.835–0.933). The data in Fig.  1 E indicated that IGF2-AS expressions can differentiate AECOPD patients from stable COPD patients with an AUC of 0.820, a cut-off value of 1.605, sensitivity of 70.00%, and specificity of 82.22% (95%CI: 0.760–0.880). Moreover, to demonstrate additive or superior diagnostic power of IGF2-AS, we combined the FEV1/FVC into the ROC curve analysis in stable COPD and AECOPD patients. The data showed that combined IGF2-AS expression and FEV1/FVC showed enhanced diagnostic value with AUC of 0.937 followed sensitivity of 88.89% and specificity of 87.78% (Table  2 ). Table 2 Analysis of diagnostic performance of different indicators in distinguishing patients with stable COPD and AECOPD Variable AUC 95%CI Sensitivity(%) Specificity(%) Youden’s index FEV1/FVC (%) 0.849 0.796–0.902 63.33 85.56 54.40 IGF2-AS expression 0.820 0.760–0.880 70.00 82.22 1.605 Combined 0.937 0.903–0.970 88.89 87.78 0.490 FEV1 forced expiratory volume in one second, COPD  Chronic obstructive pulmonary disease, AECOPD  acute exacerbation of COPD Analysis of diagnostic performance of different indicators in distinguishing patients with stable COPD and AECOPD FEV1 forced expiratory volume in one second, COPD  Chronic obstructive pulmonary disease, AECOPD  acute exacerbation of COPD To explore the effects of IGF2-AS on the pathogenesis of COPD, a COPD cell model was conducted using 2% CSE to treat 16HBE cells for 24 h. RT-qPCR showed that IGF2-AS expression was increased in the CSE-treated cell model compared to the control, the upregulation of IGF2-AS induced by CSE was reversed through transfection with IGF2-AS siRNA (Fig.  2 A). CCK-8 assay indicated that IGF2-AS knockdown reversed CSE-inhibited cell proliferation in 16HBE cells (Fig.  2 B). Moreover, the increased apoptosis induced by CSE on 16HBE cells was abolished by the downregulation of IGF2-AS (Fig.  2 C). The CSE treatment increased inflammatory cytokine (IL-1β, IL-6, and TNF-α) levels, and decreased expression of IGF2-AS diminished the effects of CSE (Fig.  2 D). Fig. 2 The effects of IGF2-AS on cellular activities and inflammatory responses in CSE-treated 16HBE cells. A  RT-qPCR analysis was utilized to detect the IGF2-AS expression in CSE-treated cells and transfected cells. B  CCK-8 assay was used to measure the influence of IGF2-AS on the proliferation of CSE-treated cells. C  Cell apoptosis assay was performed to assess the effects of IGF2-AS on cell apoptosis. D  ELISA assay was carried out to detect the concentration of inflammatory factors. *** P  < 0.001 The effects of IGF2-AS on cellular activities and inflammatory responses in CSE-treated 16HBE cells. A  RT-qPCR analysis was utilized to detect the IGF2-AS expression in CSE-treated cells and transfected cells. B  CCK-8 assay was used to measure the influence of IGF2-AS on the proliferation of CSE-treated cells. C  Cell apoptosis assay was performed to assess the effects of IGF2-AS on cell apoptosis. D  ELISA assay was carried out to detect the concentration of inflammatory factors. *** P  < 0.001 The lncRNASNP2 database predicted the binding sites between IGF2-AS and miR-106b-5p (Fig.  3 A). Dual-luciferase reporter assay indicated that upregulation of miR-106b-5p inhibited the luciferase activity of IGF2-AS-Wt vectors in 16HBE cells, and inhibition of miR-106b-5p increased the luciferase activity of IGF2-AS-Wt vectors (Fig.  3 B). Furthermore, the levels of serum miR-106b-5p were reduced in COPD patients, particularly those with AECOP (Fig.  3 C). Pearson correlation analysis displayed a negative relationship between IGF2-AS and miR-106b-5p expression in patients with AECOPD (Fig.  3 D). Fig. 3 miR-106b-5p was a direct target miRNA of IGF2-AS.  A  LncRNASNP database predicted the binding sites between IGF2-AS and miR-106b-5p. B Dual-luciferase reporter assay was utilized to confirm the binding relationship between IGF2-AS and miR-106b-5p. C  Serum miR-106b-5p was downregulated in stable COPD patients and AECOPD patients compared to healthy control. D  A negative correlation between IGF2-AS and miR-106b-5p in patients with AECOPD. ** P  < 0.01, *** P  < 0.001 miR-106b-5p was a direct target miRNA of IGF2-AS.  A  LncRNASNP database predicted the binding sites between IGF2-AS and miR-106b-5p. B Dual-luciferase reporter assay was utilized to confirm the binding relationship between IGF2-AS and miR-106b-5p. C  Serum miR-106b-5p was downregulated in stable COPD patients and AECOPD patients compared to healthy control. D  A negative correlation between IGF2-AS and miR-106b-5p in patients with AECOPD. ** P  < 0.01, *** P  < 0.001 To further confirm the IGF2-AS/miR-106b-5p axis in COPD, restoration experiments were performed. MiR-106b-5p levels were decreased in CSE-treated 16HBE cells, and increased after si-IGF2-AS transfection, while was reversed after co-transfection of miR-106b-5p inhibitor (Fig.  4 A). CCK-8 assay showed that silencing IGF2-AS improved the inhibitory impact of CSE on 16HBE cell proliferation while blocking miR-106b-5p partially attenuated the influence of si-IGF2-AS on 16HBE cells (Fig.  4 B). The CSE-induced cell apoptosis in 16HBE cells was partially abolished by si-IGF2-AS, while the effects of si-IGF2-AS were apparently attenuated by a miR-106b-5p inhibitor (Fig.  4 C and D). The inhibitory effects of IGF2-AS downregulation on CSE-induced 16HBE cell inflammatory cytokine levels were recovered by miR-106b-5p inhibition (Fig.  4 E and G). Fig. 4 Downregulation of miR-106b-5p abolished the effects of si-IGF2-AS in CSE-treated 16HBE cells. A  RT-qPCR was used to detect the miR-106b-5p expression in treatment cells. B  CCK-8 assay was used to assess cell proliferation  C and D . The effects of the IGF2-AS/miR-106b-5p axis on cell apoptosis were measured by cell apoptosis assay. E-G. The influence of the IGF2-AS/miR-106b-5p axis on inflammatory factors in CSE-treated 16HBE cells was measured by ELISA assay. ** P  < 0.01, *** P  < 0.001 Downregulation of miR-106b-5p abolished the effects of si-IGF2-AS in CSE-treated 16HBE cells. A  RT-qPCR was used to detect the miR-106b-5p expression in treatment cells. B  CCK-8 assay was used to assess cell proliferation  C and D . The effects of the IGF2-AS/miR-106b-5p axis on cell apoptosis were measured by cell apoptosis assay. E-G. The influence of the IGF2-AS/miR-106b-5p axis on inflammatory factors in CSE-treated 16HBE cells was measured by ELISA assay. ** P  < 0.01, *** P  < 0.001 The binding sites between miR-106b-5p and SIX1 were displayed in Fig.  5 A. Dual-luciferase reporter assay indicated that overexpression of miR-106b-5p suppressed the luciferase activity of SIX1-Wt vectors in 16HBE cells. Conversely, the inhibition of miR-106b-5p led to an enhancement in the luciferase activity of SIX1-Wt vectors (Fig.  5 B. Moreover, the expression of SIX1 was upregulated in CSE-treated cells. Transfection with si-IGF2-AS partially restored SIX1 levels, whereas co-transfection with miR-106b-5p inhibitor abolished this effect (Fig.  5 C). Fig. 5 The target relationship between miR-106b-5p and SIX1.  A  The binding sites between miR-106b-5p and SIX1.  B  Dual-luciferase reporter assay verified the target interaction between miR-106b-5p and SIX1. C  The SIX1 mRNA levels were detected after GSE treatment and co-transfection of miR-106b-5p and SIX1 The target relationship between miR-106b-5p and SIX1.  A  The binding sites between miR-106b-5p and SIX1.  B  Dual-luciferase reporter assay verified the target interaction between miR-106b-5p and SIX1. C  The SIX1 mRNA levels were detected after GSE treatment and co-transfection of miR-106b-5p and SIX1

A total of 90 patients with acute exacerbation of COPD (AECOPD) who were treated in Geriatric Hospital Affiliated to Wuhan University of Science and Technology from March 2021 to June 2023 were selected as the AECOPD group, and 90 patients with stable COPD who were re-examined in the outpatient department were selected as the stable COPD group. During the same period, 90 healthy volunteers who participated in the physical examination were selected as the control group. The inclusion criteria were as follows: (1) The patients met the diagnostic criteria of acute exacerbation and stable COPD respectively, (2) the patients were diagnosed by pulmonary function test and arterial blood gas analysis, with forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) < 70% after bronchodilator inhalation, (3) patients with complete clinical information. Exclusion criteria: (1) patients who were accompanied by bronchial disease, asthma, apnea syndrome, and other respiratory diseases were excluded, (2) patients accompanied with malignant tumors or serious damage to important organs such as heart, liver, and kidney were excluded. All participants provided signed informed consent, and the research was approved by the hospital’s Medical Ethics Committee. On the next day of admission, the fasting peripheral venous blood samples were collected from COPD patients using EDTA anticoagulated blood collection tubes. Besides, the fasting blood samples were collected from stable COPD patients and controls during reexamination or physical examination. The blood was centrifuged to collect the serum samples, which were stored at −80 °C freezer for use. A human normal bronchial epithelial cell line (16HBE) was used in this study, which was purchased from Pricella Biotechnology Co., Ltd. (Wuhan, China). The cells were cultured in RPMI-1640 medium (Invitrogen, USA) blended with 10% FBS (Invitrogen) in a humidified incubator with 5% CO 2 at 37 °C. To establish the COPD model, 16HBE cells were treated with 2% cigarette smoke extract (CSE) as previously described [ 16 ]. siRNA against IGF2-AS (si-IGF2-AS), siRNA negative control (si-NC), miR-106b-5p mimic, mimic NC, miR-106b-5p inhibitor, and inhibitor NC were constructed by Gene Pharma (Shanghai, China). Transfection or co-transfection was progressed utilizing Lipofectamine 2000 (Invitrogen). Total RNAs were extracted from serum samples and cells utilizing TRIzol reagent (Invitrogen). The concentration and purity of total RNA were determined before reverse transcription. The RNA samples were reversed into cDNA with the help of PrimeScript RT Reagent Kit (TaKaRa, Dalian, China). Then, qPCR was carried out using SYBR Premix Ex Taq reagent (TaKaRa) on an ABI PRISM 7000 fluorescent quantitative PCR system (Applied Biosystems). The expression levels of lncRNA or miRNA are determined by 2 −ΔΔCt approach, utilizing GAPDH or U6 as the internal control. The CCK-8 assay (Beyotime, Shanghai, China) was employed to assess cell viability. Briefly, treated cells (5000 cells/well) were plated in 96-well plates and cultured for 0, 24, 48, and 72 h. Then, CCK-8 solution was added to each well at different time points. Following a 1-hour incubation period, the absorbance at 450 nm for each cell group was recorded using a microplate reader (BioTeck). The effects of IGF2-AS on apoptosis of 16HBE cells were assessed using the flow cytometry assay at 48 h of transfection. The cells (5 × 10 4 cells) were seeded into 6-well plates. Post-treatment, the cells were re-suspended and subjected to staining with Annexin V-fluorescein isothiocyanate (FITC) and Propidium Iodide (PI) from Beyotime, incubated in the dark for a duration of 10 min. Subsequently, the apoptosis rate was quantified using flow cytometry (BD Bioscience, USA) and analyzed with FlowJo software (TreeStar, USA). The concentrations of inflammatory cytokines, including IL-1β, IL-6, and TNF-a, were measured in cell culture supernatants using Enzyme-Linked Immunosorbent Assays (ELISA) (Elabscience, Wuhan, China). The online database lncRNASNP2 ( https://guolab.wchscu.cn/lncRNASNP/#!/ ) was utilized to predict the downstream miRNAs of IGF2-AS and displayed the binding sites between IGF2-AS and miR-106b-5p. Fragments of the wild type (Wt) and mutant (Mutant) IGF2-AS or SIX1, encompassing the miR-106b-5p binding sites, were synthesized and ligated into the psiCHECK-2 luciferase reporter vector (Promega), resulting in the creation of the IGF2-AS-Wt and IGF2-AS-Mut vectors, as well as SIX1-Wt and SIX1-Mut vectors. The vectors, along with miR-106b-5p mimic, inhibitor, or respective negative controls (NCs) were co-transfected into 16HBE cells using Lipofectamine 2000 for 48 h. Then, the luciferase activities were assessed with a dual luciferase reporter assay system (Promega). Statistical evaluations were performed using GraphPad Prism 9.0 software. Data were depicted as mean ± SD, derived from a minimum of three independent experiments. Comparisons between/among groups were assessed using an unpaired Student t-test or one-way analysis of variance (ANOVA). Pearson’s correlation method was employed for correlation analysis. To assess the diagnostic utility of IGF2-AS in COPD, a receiver operating characteristic (ROC) curve was generated. Statistical significance was set at a P -value below 0.05.

COPD is a complex heterogeneous disorder, which has dysregulated metabolites arise [ 17 – 19 ], pathological inflammation, as well as dysregulation of some of disease relevant ncRNAs [ 20 ]. Accumulating evidence has demonstrated that lncRNA could participate in the progression of diseases [ 21 , 22 ]. LncRNA IGF2-AS was found to be aberrantly expressed in various forms of cancer. For instance, IGF2-AS displays high expression in pancreatic cancer and facilitates tumor progression by regulating IGF2 expression [ 23 ]. IGF2-AS was also upregulated in endometriosis, which could facilitate endometriotic cell growth by regulating miR-370-3p/IGF2 axis [ 24 ]. However, the clinical significance and underlying mechanisms of IGF2-AS in COPD remain elusive. Increasing evidence indicated the functional role of lncRNAs in COPD [ 25 , 26 ]. For instance, increased lncRNA H19 induced smoke-related COPD-mediated lung injury by regulating miR-181/PDCD4 axis [ 27 ]. Enhanced expression of serum lncRNA XIST has diagnostic value for screening COPD and predicting adverse prognosis of COPD patients with pulmonary heart disease [ 28 ]. In the current study, serum IGF2-AS expression was elevated in COPD patients, and correlated with the severity of the diseases, especially in patients with AECOPD, which suggested that IGF2-AS might participate in the progression of COPD. Consistently, a recent ceRNA network study has mentioned that IGF2-AS was one of the upregulated lncRNAs in COPD [ 11 ]. Differently expressed lncRNAs showed their key role in the diagnostic and prognostic value of COPD [ 25 , 29 , 30 ]. Based on the upregulation levels of IGF2-AS in patients with stable COPD and AECOPD, we further evaluated its clinical diagnostic value. Herein, increased expression of IGF2-AS could distinguish stable COPD patients from healthy control, as well as differentiate AECOPD patients from stable COPD patients, with relatively high sensitivity and specificity. Therefore, elevated expression of IGF2-AS might be a diagnostic indicator in the clinical early screening of COPD from healthy individuals and AECOPD from stable COPD patients. Additionally, combined clinical indicator FEV1/FVC and IGF2-AS expression displayed higher diagnostic significance than both alone. However, the clinical significance of IGF2-AS and the specific cutoff need to be further validated in larger clinical cohorts. Previous research indicated that IGF2-AS regulated cell growth, apoptosis, and inflammatory response in several diseases [ 10 , 31 , 32 ]. To further explore the functional role of IGF2-AS in COPD, the COPD cell model was conducted using 16HBE cells that were treated with 2% CSE. Cellular experiments indicated that CSE treatment inhibited 16HBE cell proliferation and induced cell apoptosis. Silencing IGF2-AS abolished the effects of CSE on the cellular activities of 16HBE cells. The bronchial epithelium in patients with COPD often presents chronic inflammatory changes. Herein, the concentrations of inflammatory cytokines IL-1β, IL-6, and TNF-α notably rose after CSE exposure, while the effects were diminished by IGF2-AS downregulation. These data underscore the important role of IGF2-AS in COPD. At present, it is believed that miRNA, lncRNA, and mRNA can regulate each other through multiple sites and targets to affect the occurrence of diseases. Previous studies indicated that IGF2-AS could participate in diseases by targeting miRNAs, such as miR-370-3p, miR-530, miR-3126-5p, and miR-195 [ 9 , 24 , 33 , 34 ]. In this study, bioinformatics analysis and luciferase reporter assay verified that miR-106b-5p could bind to IGF2-AS. miR-106b-5p was abnormally expressed in lung diseases, such as chronic obstructive pulmonary disease and COPD [ 15 , 35 ]. It is speculated that in 16HBE cells, IGF2-AS might regulate CSE-induced cell behaviors and inflammatory response by targeting miR-106b-5p. miR-106b-5p has been extensively studied in various diseases, such as cancers, coronary artery disease, and acute kidney injury [ 36 – 38 ]. Consistent with a previous study [ 15 ], serum miR-106b-5p was downregulated in patients with COPD. Restoration experiments indicated that inhibition of miR-106b-5p partially reversed the functional effects and inflammatory response of IGF2-AS knockdown on CSE-treated 16HBE cells. These results suggest that miR-106b-5p may inhibit the inflammatory response by negatively regulating the expression of IL-6 and TNF during CSE exposure. However, the effects of miR-106b-5p inhibitor may be influenced by a variety of factors, such as dose, exposure time, and cell type. A previous study indicated that miR-106b-5p expression was decreased in asthma mice and TGF-β1-induced BEAS-2B cells and could target Sine oculis homeobox homolog 1 (SIX1) to repress TGF-β1-induced pulmonary fibrosis and epithelial-mesenchymal transition in asthma through E2F1/SIX1 signaling pathway [ 39 ]. Current study verified the target relationship between miR-106b-5p and SIX1 in 16HBE cells, suggesting miR-106b-5p might have regulatory effects on SIX1 in COPD. SIX1 is upregulated in idiopathic pulmonary fibrosis and plays critical role in pulmonary fibrosis [ 40 ]. The elevated expression of SIX1 was observed in the lungs in an OVA mouse model of allergic asthma and was involved in the EMT processes of airway remodeling in asthma through TGF-β1/Smad signaling pathway [ 33 ]. Combined with the results of previous studies and the results of this study, we speculated that IGF2-AS might influence the occurrence and progression of COPD by regulating miR-106b-5p through SIX1/TGF-β1/Smad signaling pathway. However, there are still some shortcomings in this study. For instance, while IGF2-AS upregulation in COPD was observed, the specific respiratory cell types (e.g., alveolar epithelial cells, bronchial smooth muscle cells) and immune cell subsets (e.g., macrophages, T lymphocytes) driving this expression remain undefined. Second, patient heterogeneity was not fully addressed—factors like comorbid asthma or systemic inflammation profiles, may influence IGF2-AS-mediated pathways. Third, smoking history (e.g., pack-years, current/former smoking status), a key COPD risk factor, was not stratified in the analysis, potentially confounding IGF2-AS expression correlations. The functional role of IGF-AS/miR-106b-5p in COPD was investigated in cell models. Their role in vivo models remains unverified, thus, we are committed to addressing this in future research after obtaining the approvals from ethical review boards. Lastly, the detailed mechanism of IGF2-AS in COPD is not completely clear, which needs to be further confirmed and explored by cell function experiments of target genes and in vivo experiments. In conclusion, serum IGF2-AS was upregulated in patients with COPD, especially in patients with AECOPD, and correlated with the severity of COPD. The increased IGF2-AS might be a diagnostic biomarker in predicting patients with AECOPD from patients with stable COPD, as well as healthy individuals. IGF2-AS expressions participated in the pathogenesis and inflammation of COPD by regulating miR-106b-5p, which might elaborate a novel mechanism in managing COPD. For translational implementation, standardized detection assays (e.g., qPCR or ELISA) must be validated across multi-center cohorts to ensure reproducibility. This step is critical to address assay variability that could hinder clinical adoption. Regulatory pathways, such as clinical trials evaluating IGF2-AS as a diagnostic adjunct or therapeutic target, will require collaboration with agencies. Future studies should prioritize large-scale cohort validation, integration with clinical decision algorithms, and preclinical trials to assess IGF2-AS-targeted interventions, thereby translating mechanistic insights into actionable diagnostics and therapies for COPD management.

Most cases of chronic obstructive pulmonary disease (COPD) are primarily due to the inhalation of harmful gases. The disease is characterized by abnormal airway inflammation, destruction of alveolar structure and function, and airway remodeling [ 1 ]. The persistent airflow limitation and incomplete reversible decline in lung function represent the primary clinical changes in COPD that render it incapable of full recovery. The prevalence of COPD in people over 40 years old in China is as high as 13.6% in 2014-15 [ 2 ]. Although the total number of COPD has been decreasing over the past decades, COPD remains a substantial public health concern in the country [ 3 ]. Clinically, COPD patients at different stages will be given different treatment options, and the current clinical diagnosis of acute exacerbation of COPD (AECOPD) patients easily misjudged and delayed the best treatment opportunity [ 4 ]. Therefore, it is of great significance to search for indicators that can effectively evaluate the occurrence of AECOPD patients. Long non-coding RNA (lncRNA), transcripts exceeding 200 nucleotides in length, are pivotal in regulating cellular biology and disease development [ 5 ]. The abnormal expression of lncRNAs could regulate cell growth, apoptosis, and differentiation processes, which provided a new direction for molecular diagnosis and gene therapy of diseases [ 6 , 7 ]. Increasing studies showed that dysregulated lncRNA expressions are involved in the progression of COPD. For instance, lncRNA GAS5 expression was increased in COPD and promoted pyroptosis by modulating the miR-223-3p/NLRP3 axis in COPD [ 8 ]. LncRNA insulin-like growth factor 2 antisense transcripts (IGF2-AS), located on chromosome 11, have been extensively validated in many diseases, such as gastric cancer and sepsis [ 9 , 10 ]. A study based on lncRNA microarray data indicated that IGF2-AS1 was an upregulated lncRNA in COPD patients [ 11 ]. Based on the above evidence, it is speculated that IGF2-AS is relevant to the progression of POCD. The dysregulation of miR-106b-5p was reported in many tumors and diseases that played different roles [ 12 , 13 ]. For instance, miR-106b-5p was downregulated in acute pulmonary embolism mice and regulated the proliferation of platelet‑derived growth factor‑induced pulmonary artery smooth muscle cells [ 14 ]. miR-106b-5p was reported to be downregulated and might have clinical relevance in COPD [ 15 ]. The role of miR-106b-5p in COPD remains elusive. LncRNAs typically play their functional effects by regulating miRNAs. The exact role of IGF2-AS in COPD, particularly in its regulation of miR-106b-5p, is yet to be elucidated. In the current study, we examined IGF2-AS function and its clinical performance, as well as its molecular mechanism in COPD. We hypothesized that IFG2-AS may trigger apoptosis and inflammatory response of bronchial epithelial cells by modulating miR-106b-5p. These data might provide novel therapeutic strategies for treating COPD.

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