Shared genetic aetiology of respiratory diseases: a genome-wide multitraits association analysis.

OBJECTIVE: This study aims to explore the common genetic basis between respiratory diseases and to identify shared molecular and biological mechanisms. METHODS: This genome-wide pleiotropic association study uses multiple statistical methods to systematically analyse the shared genetic basis between five respiratory diseases (asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, lung cancer and snoring) using the largest publicly available genome wide association studies summary statistics. The missions of this study are to evaluate global and local genetic correlations, to identify pleiotropic loci, to elucidate biological pathways at the multiomics level and to explore causal relationships between respiratory diseases. Data were collected from 27 November 2022 to 30 March 2023 and analysed from 14 April 2023 to 13 July 2023. MAIN OUTCOMES AND MEASURES: The primary outcomes are shared genetic loci, pleiotropic genes, biological pathways and estimates of genetic correlations and causal effects. RESULTS: Significant genetic correlations were found for 10 paired traits in 5 respiratory diseases. Cross-Phenotype Association identified 12 400 significant potential pleiotropic single-nucleotide polymorphism at 156 independent pleiotropic loci. In addition, multitrait colocalisation analysis identified 15 colocalised loci and a subset of colocalised traits. Gene-based analyses identified 432 potential pleiotropic genes and were further validated at the transcriptome and protein levels. Both pathway enrichment and single-cell enrichment analyses supported the role of the immune system in respiratory diseases. Additionally, five pairs of respiratory diseases have a causal relationship. CONCLUSIONS AND RELEVANCE: This study reveals the common genetic basis and pleiotropic genes among respiratory diseases. It provides strong evidence for further therapeutic strategies and risk prediction for the phenomenon of respiratory disease comorbidity.

HTR2B as a novel biomarker of chronic obstructive pulmonary disease with lung squamous cell carcinoma.

Chronic obstructive pulmonary disease (COPD) is often associated with lung squamous cell carcinoma (LUSC), which has the same etiology (smoking, inflammation, oxidative stress, microenvironmental changes, and genetics). Smoking, inflammation, and airway remodeling are the most important and classical mechanisms of COPD comorbidity in LUSC patients. Cancer can occur during repeated airway damage and repair (airway remodeling). Changes in the inflammatory and immune microenvironments, which can cause malignant transformation of some cells, are currently being revealed in both LUSC and COPD patients. We obtained the GSE76925 dataset from the Gene Expression Omnibus database. Screening for possible COPD biomarkers was performed using the LASSO regression model and a random forest classifier. The compositional patterns of the immune cell fraction in COPD patients were determined using CIBERSORT. HTR2B expression was analyzed using validation datasets (GSE47460, GSE106986, and GSE1650). HTR2B expression in COPD cell models was determined via real-time quantitative PCR. Epithelial-mesenchymal transition (EMT) marker expression levels were determined after knocking down or overexpressing HTR2B. HTR2B function and mechanism in LUSC were analyzed with the Kaplan‒Meier plotter database. HTR2B expression was inhibited to detect changes in LUSC cell proliferation. A total of 1082 differentially expressed genes (DEGs) were identified in the GSE76925 dataset (371 genes were significantly upregulated, and 711 genes were significantly downregulated). Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis indicated that the DEGs were mainly enriched in the p53 signaling and ß-alanine metabolism pathways. Gene Ontology enrichment analysis indicated that the DEGs were largely related to transcription initiation from the RNA polymerase I promoter and to the regulation of mononuclear cell proliferation. The LASSO regression model and random forest classifier results revealed that HTR2B, DPYS, FRY, and CD19 were key COPD genes. Immune cell infiltration analysis indicated that these genes were closely associated with immune cells. Analysis of the validation sets suggested that HTR2B was upregulated in COPD patients. HTR2B was significantly upregulated in COPD cell models, and its upregulation was associated with increased EMT marker expression. Compared with that in bronchial epithelial cells, HTR2B expression was upregulated in LUSC cells, and inhibiting HTR2B expression led to the inhibition of LUSC cell proliferation. In conclusions, HTR2B might be a new biomarker and therapeutic target in COPD patients with LUSC.

Multi-center Korean cohort study based on RNA-sequencing data targeting COPD patients.

In 2023, WHO ranked chronic obstructive pulmonary disease (COPD) as the third leading cause of death, with 3.23 million fatalities in 2019. The intricate nature of the disease, which is influenced by genetics, environment, and lifestyle, is evident. The effect of air pollution and changes in atmospheric substances because of global warming highlight the need for this research. These environmental shifts are associated with the emergence of various respiratory infections such as COVID-19. RNA sequencing is pivotal in airway diseases, including COPD, as it enables comprehensive transcriptome analysis, biomarker discovery, and uncovers novel pathways. It facilitates personalized medicine by tracking dynamic changes in gene expression in response to various triggers. However, the limited research on East Asian populations may overlook the unique nuances of COPD development and progression. Bridging this gap and using peripheral blood samples for systemic analysis are crucial for comprehensive and globally applicable COPD diagnosis and treatment.

Long non-coding RNA Small Nucleolar RNA Host Gene 4 ameliorates cigarette smoke-induced proliferation, apoptosis, inflammation, and airway remodeling in alveolar epithelial cells through the modulation of the mitogen-activated protein kinase signaling pathway via the microRNA-409-3p/Four and a Half LIM Domains 1 axis.

The long non-coding RNA (lncRNA) Small Nucleolar RNA Host Gene 4 (SNHG4) has been demonstrated to be significantly downregulated in various inflammatory conditions, yet its role in chronic obstructive pulmonary disease (COPD) remains elusive. This study aims to elucidate the biological function of SNHG4 in COPD and to unveil its potential molecular targets. Our findings reveal that both SNHG4 and Four and a Half LIM Domains 1 (FHL1) were markedly downregulated in COPD, whereas microRNA-409-3p (miR-409-3p) was upregulated. Importantly, SNHG4 exhibited a negative correlation with inflammatory markers in patients with COPD, but a positive correlation with forced expiratory volume in 1s percentage (FEV1%). SNHG4 distinguished COPD patients from non-smokers with high sensitivity, specificity, and accuracy. Overexpression of SNHG4 ameliorated cigarette smoke extract (CSE)-mediated inflammation, apoptosis, oxidative stress, and airway remodeling in 16HBE bronchial epithelial cells. These beneficial effects of SNHG4 overexpression were reversed by the overexpression of miR-409-3p or the silencing of FHL1. Mechanistically, SNHG4 competitively bound to miR-409-3p, mediating the expression of FHL1, and consequently improving inflammation, apoptosis, oxidative stress, and airway remodeling in 16HBE cells. Additionally, SNHG4 regulated the miR-409-3p/FHL1 axis to inhibit the activation of the mitogen-activated protein kinase (MAPK) pathway induced by CSE. In a murine model of COPD, knockdown of SNHG4 exacerbated CSE-induced pulmonary inflammation, apoptosis, and oxidative stress. In summary, our data affirm that SNHG4 mitigates pulmonary inflammation, apoptosis, and oxidative damage mediated by COPD through the regulation of the miR-409-3p/FHL1 axis.

A miRNA-21-Mediated PTEN/Akt/NF-κB Axis Promotes Chronic Obstructive Pulmonary Disease Pathogenesis.

Background: This study sought to explore the underlying mechanism of miR-21 mediated apoptosis and inflammation in chronic obstructive pulmonary disease (COPD) induced by cigarette smoke (CS). Methods: We detected levels and PTEN/Akt/NF-κB axis protein levels in peripheral lung tissues of COPD patients and CS-exposed mice and HBE cells. Western blotting assay was used to determine the expression of cleaved caspase-3. IL-6 and IL-8 protein was detected in cell supernatant from cells by ELISA. HBE cells were transfected with a miR-21 inhibitor, and co-culture with A549. Results: Increased miR-21 expression, reduced PTEN expression and following activation of Akt in in peripheral lung tissues of COPD patients and CS-exposed mice and HBE cells. Inhibition of miR-21 showed enhanced PTEN levels and reduced the expression of phosphorylated form of Akt and NF-κB. Decreased expression of cleaved caspase-3, IL-6 and IL-8 in A549 cells co cultured with HBE cells transfected with miR-21 inhibitor compared with transfected with miR-21 control inhibitor. Conclusion: MiR-21 contributes to COPD pathogenesis by modulating apoptosis and inflammation through the PTEN/Akt/NF-κB pathway. Targeting miR-21 may increase PTEN expression and inhibit Akt/NF-κB pathway, offering potential diagnostic and therapeutic value in COPD management.

Periodontal disease increases the severity of chronic obstructive pulmonary disease: a Mendelian randomization study.

BACKGROUND: Recent research suggests that periodontitis can increase the risk of chronic obstructive pulmonary disease (COPD). In this study, we performed two-sample Mendelian randomization (MR) and investigated the causal effect of periodontitis (PD) on the genetic prediction of COPD. The study aimed to estimate how exposures affected outcomes. METHODS: Published data from the Gene-Lifestyle Interaction in the Dental Endpoints (GLIDE) Consortium's genome-wide association studies (GWAS) for periodontitis (17,353 cases and 28,210 controls) and COPD (16,488 cases and 169,688 controls) from European ancestry were utilized. This study employed a two-sample MR analysis approach and applied several complementary methods, including weighted median, inverse variance weighted (IVW), and MR-Egger regression. Multivariable Mendelian randomization (MVMR) analysis was further conducted to mitigate the influence of smoking on COPD. RESULTS: We chose five single-nucleotide polymorphisms (SNPs) as instrumental variables for periodontitis. A strong genetically predicted causal link between periodontitis and COPD, that is, periodontitis as an independent risk factor for COPD was detected. PD (OR = 1.102951, 95% CI: 1.005-1.211, p = 0.039) MR-Egger regression and weighted median analysis results were coincident with those of the IVW method. According to the sensitivity analysis, horizontal pleiotropy's effect on causal estimations seemed unlikely. However, reverse MR analysis revealed no significant genetic causal association between COPD and periodontitis. IVW (OR = 1.048 > 1, 95%CI: 0.973-1.128, p = 0.2082) MR Egger (OR = 0.826, 95%CI:0.658-1.037, p = 0.1104) and weighted median (OR = 1.043, 95%CI: 0.941-1.156, p = 0.4239). The results of multivariable Mendelian randomization (MVMR) analysis, after adjusting for the confounding effect of smoking, suggest a potential causal relationship between periodontitis and COPD (P = 0.035). CONCLUSION: In this study, periodontitis was found to be independent of COPD and a significant risk factor, providing new insights into periodontitis-mediated mechanisms underlying COPD development.

Roles of glutamic pyruvate transaminase 2 in reprogramming of airway epithelial lipidomic and metabolomic profiles after smoking.

Metabolic abnormalities represent one of the pathological features of chronic obstructive pulmonary disease (COPD). Glutamic pyruvate transaminase 2 (GPT2) is involved in glutamate metabolism and lipid synthesis pathways, whilst the exact roles of GPT2 in the occurrence and development of COPD remains uncertain. This study aims at investigating how GPT2 and the associated genes modulate smoking-induced airway epithelial metabolism and damage by reprogramming lipid synthesis. The circulating or human airway epithelial metabolomic and lipidomic profiles of COPD patients or cell-lines explored with smoking were assessed to elucidate the pivotal roles of GPT2 in reprogramming processes. We found that GPT2 regulate the reprogramming of lipid metabolisms caused by smoking, especially phosphatidylcholine (PC) and triacylglycerol (TAG), along with changes in the expression of lipid metabolism-associated genes. GPT2 modulated cell sensitivities and survival in response to smoking by enhancing mitochondrial functions and maintaining lipid and energy homeostasis. Our findings provide evidence for the involvement of GPT2 in the reprogramming of airway epithelial lipids following smoking, as well as the molecular mechanisms underlying GPT2-mediated regulation, which may offer an alternative of therapeutic strategies for chronic lung diseases.

MicroRNA-26a in respiratory diseases: mechanisms and therapeutic potential.

MicroRNAs (miRNAs) are short, non-coding single-stranded RNA molecules approximately 22 nucleotides in length, intricately involved in post-transcriptional gene expression regulation. Over recent years, researchers have focused keenly on miRNAs, delving into their mechanisms in various diseases such as cancers. Among these, miR-26a emerges as a pivotal player in respiratory ailments such as pneumonia, idiopathic pulmonary fibrosis, lung cancer, asthma, and chronic obstructive pulmonary disease. Studies have underscored the significance of miR-26a in the pathogenesis and progression of respiratory diseases, positioning it as a promising therapeutic target. Nevertheless, several challenges persist in devising medical strategies for clinical trials involving miR-26a. In this review, we summarize the regulatory role and significance of miR-26a in respiratory diseases, and we analyze and elucidate the challenges related to miR-26a druggability, encompassing issues such as the efficiency of miR-26a, delivery, RNA modification, off-target effects, and the envisioned therapeutic potential of miR-26a in clinical settings.

Genetic variations in anti-diabetic drug targets and COPD risk: evidence from mendelian randomization.

BACKGROUND: Previous research has emphasized the potential benefits of anti-diabetic medications in inhibiting the exacerbation of Chronic Obstructive Pulmonary Disease (COPD), yet the role of anti-diabetic drugs on COPD risk remains uncertain. METHODS: This study employed a Mendelian randomization (MR) approach to evaluate the causal association of genetic variations related to six classes of anti-diabetic drug targets with COPD. The primary outcome for COPD was obtained from the Global Biobank Meta-analysis Initiative (GBMI) consortium, encompassing a meta-analysis of 12 cohorts with 81,568 cases and 1,310,798 controls. Summary-level data for HbA1c was derived from the UK Biobank, involving 344,182 individuals. Positive control analysis was conducted for Type 2 Diabetes Mellitus (T2DM) to validate the choice of instrumental variables. The study applied Summary-data-based MR (SMR) and two-sample MR for effect estimation and further adopted colocalization analysis to verify evidence of genetic variations. RESULTS: SMR analysis revealed that elevated KCNJ11 gene expression levels in blood correlated with reduced COPD risk (OR = 0.87, 95% CI = 0.79-0.95; p = 0.002), whereas an increase in DPP4 expression corresponded with an increased COPD incidence (OR = 1.18, 95% CI = 1.03-1.35; p = 0.022). Additionally, the primary method within MR analysis demonstrated a positive correlation between PPARG-mediated HbA1c and both FEV1 (OR = 1.07, 95% CI = 1.02-1.13; P = 0.013) and FEV1/FVC (OR = 1.08, 95% CI = 1.01-1.14; P = 0.007), and a negative association between SLC5A2-mediated HbA1c and FEV1/FVC (OR = 0.86, 95% CI = 0.74-1.00; P = 0.045). No colocalization evidence with outcome phenotypes was detected (all PP.H4 < 0.7). CONCLUSION: This study provides suggestive evidence for anti-diabetic medications' role in improving COPD and lung function. Further updated MR analyses are warranted in the future, following the acquisition of more extensive and comprehensive data, to validate our results.

Genetic association of inflammatory marker GlycA with lung function and respiratory diseases.

Association of circulating glycoprotein acetyls (GlycA), a systemic inflammation biomarker, with lung function and respiratory diseases remain to be investigated. We examined the genetic correlation, shared genetics, and potential causality of GlycA (N = 115,078) with lung function and respiratory diseases (N = 497,000). GlycA showed significant genetic correlation with FEV1 (rg = -0.14), FVC (rg = -0.18), asthma (rg = 0.21) and COPD (rg = 0.31). We consistently identified ten shared loci (including chr3p21.31 and chr8p23.1) at both SNP and gene level revealing potential shared biological mechanisms involving ubiquitination, immune response, Wnt/ß-catenin signaling, cell growth and differentiation in tissues or cells including blood, epithelium, fibroblast, fetal thymus, and fetal intestine. Genetically elevated GlycA was significantly correlated with lung function and asthma susceptibility (354.13 ml decrement of FEV1, 442.28 ml decrement of FVC, and 144% increased risk of asthma per SD increment of GlycA) from MR analyses. Our findings provide insights into biological mechanisms of GlycA in relating to lung function, asthma, and COPD.

Potential marker genes for chronic obstructive pulmonary disease revealed based on single-cell sequencing and Mendelian randomization analysis.

BACKGROUND: Progress is being made in the prevention and treatment of chronic obstructive pulmonary disease (COPD), but it is still unsatisfactory. With the development of genetic technology, validated genetic information can better explain COPD. OBJECTIVE: The study utilized scRNA-seq and Mendelian randomization analysis of eQTLs to identify crucial genes and potential mechanistic pathways underlying COPD pathogenesis. MEHODS: Single-cell sequencing data were used to identify marker genes for immune cells in the COPD process. Data on eQTLs for immune cell marker genes were obtained from the eQTLGen consortium. To estimate the causal effect of marker genes on COPD, we selected an independent cohort (ukb-b-16751) derived from the UK Biobank database for two-sample Mendelian randomization analysis. Subsequently, we performed immune infiltration analysis, gene set enrichment analysis (GSEA), and co-expression network analysis on the key genes. RESULTS: The 154 immune cell-associated marker genes identified were mainly involved in pathways such as vacuolar cleavage, positive regulation of immune response and regulation of cell activation. Mendelian randomization analysis screened four pairs of marker genes (GZMH, COTL1, CSTA and CD14) were causally associated with COPD. These four key genes were significantly associated with immune cells. In addition, we have identified potential transcription factors associated with these key genes using the Cistrome database, thus contributing to a deeper understanding of the regulatory network of these gene expressions. CONCLUSIONS: This eQTLs Mendelian randomization study identified four key genes (GZMH, COTL1, CSTA, and CD14) causally associated with COPD, providing new insights for prevention and treatment of COPD.

Chronic Obstructive Pulmonary Disease Exacerbations Increase the Risk of Subsequent Cardiovascular Events: A Longitudinal Analysis of the COPDGene Study.

BACKGROUND: Cardiovascular disease (CVD) is the most important comorbidity in patients with chronic obstructive pulmonary disease (COPD). COPD exacerbations not only contribute to COPD progression but may also elevate the risk of CVD. This study aimed to determine whether COPD exacerbations increase the risk of subsequent CVD events using up to 15 years of prospective longitudinal follow-up data from the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) study. METHODS AND RESULTS: The COPDGene study is a large, multicenter, longitudinal investigation of COPD, including subjects at enrollment aged 45 to 80 years with a minimum of 10 pack-years of smoking history. Cox proportional hazards models and Kaplan-Meier survival curves were used to assess the risk of a composite end point of CVD based on the COPD exacerbation rate. Frequent exacerbators exhibited a higher cumulative incidence of composite CVD end points than infrequent exacerbators, irrespective of the presence of CVD at baseline. After adjusting for covariates, frequent exacerbators still maintained higher hazard ratios (HRs) than the infrequent exacerbator group (without CVD: HR, 1.81 [95% CI, 1.47-2.22]; with CVD: HR, 1.92 [95% CI, 1.51-2.44]). This observation remained consistently significant in moderate to severe COPD subjects and the preserved ratio impaired spirometry population. In the mild COPD population, frequent exacerbators showed a trend toward more CVD events. CONCLUSIONS: COPD exacerbations are associated with an increased risk of subsequent cardiovascular events in subjects with and without preexisting CVD. Patients with COPD experiencing frequent exacerbations may necessitate careful monitoring and additional management for subsequent potential CVD. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00608764.

SNP-SNP positive interaction between MMP2 and MMP12 increases the risk of COPD.

Determining SNP-SNP interaction of the disease has become important for further investigation of pathogenesis and experimental research. Although many studies have been published on the effect of MMPs gene polymorphisms on chronic obstructive pulmonary disease (COPD), there is a lack of information on SNP-SNP and SNP-environment interactions. This study aimed to investigate the interaction between the polymorphisms of MMP1, MMP2, MMP9 and MMP12 genes and its combined effect with smoking on the risk of developing COPD. Totally 181 COPD patients and 292 healthy individuals were involved. Blood samples from the participants were tested for genotyping and data were collected through questionnaires. Genotyping was performed with nested allele-specific polymerase chain reaction (AS-PCR) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). SNP-SNP and SNP-environment interactions were investigated using multifactor dimensionality reduction and logistic regression analysis. The result showed that participants with high nicotine dependence and heavy smokers had a higher risk of COPD than non-smokers. Also, G/G genotype (cOR = 5.83; 95% CI, 1.19-28.4, p = 0.029) of MMP2 rs243864 and T/T genotype (cOR = 1.79; 95% CI, 1.16-2.76, p = 0.008) of MMP12 rs652438 independently contributes to the susceptibility of COPD. For SNP-SNP interaction, the positive interaction between rs243864 G/G genotype of MMP2 and rs652438 T/T genotype of MMP12 was found, and the combination of risk genotypes has a high risk of COPD (OR = 12.92; 95% CI, 1.46-114.4, p = 0.021). Moreover, the combination of T/T genotype of MMP12 rs652438 and smoking-related factors increases the risk of COPD approximately 4.5 to 6-fold. The results suggests that there is a combination of MMP2, MMP12, and smoking-related factors may increase the risk of developing COPD.

Identification of related-genes of T cells in lung tissue of chronic obstructive pulmonary disease based on bioinformatics and experimental validation.

T cells are one of the main cell types shaping the immune microenvironment in chronic obstructive pulmonary disease (COPD). They persist andplay cytotoxic roles. The purpose of this study aimed to explore the potential related-genes of T cells in lung tissue of COPD. Chip data GSE38974 and single_celldata GSE196638 were downloaded from the GEO database. Difference analyses and WGCNA of GSE38974 were performed to identify DEGs and the modules most associated with the COPD phenotype. Various cell subsets were obtained by GSE196638, and DEGs of T cells were further identified. GO, GSEA and KEGG enrichment analyses were conducted to explore the biological functions and regulatory signaling pathways of the DEGs and DEGs of T cells. The intersection of the DEGs, module genes and DEGs of T cells was assessed to acquire related-genes of T cells. The mRNA and protein expression levels of related-genes ofT cells were verified in lung tissue of mouse with emphysema model. Based on GSE38974 difference analysis, 3811 DEGs were obtained. The results of WGCNA showed that the red module had the highest correlation coefficient with the COPD phenotype. GSE196638 analysis identified 124 DEGs of T cells. The GO, GSEAand KEGG enrichment analyses mainly identified genes involved in I-kappaB kinase/NF-kappaB signaling, receptor signaling pathway via STAT, regulationof CD4-positive cells, regulation of T-helper cell differentiation, chemokine signaling pathway, Toll-likereceptor signaling pathway, CD8-positive cells, alpha-beta T cell differentiation, MAPK signaling pathway and Th17 cell differentiation. The DEGs, genes of the red module and DEGs of T cells were overlapped to acquire FOXO1 and DDX17. The results of RT-qPCR and Western Blot indicate that the mRNA and protein expression levels of FOXO1 and DDX17 in lung tissue of emphysema mice were significantly higher compared with those in air-exposed mice. FOXO1 as well as DDX17 may be related-genesof T cells in lung tissue of patient with COPD, and their participation in the biological processes of different signaling pathways may inspire further COPD research.

FBXL19 Targeted STK11 Degradation Enhances Cigarette Smoke-Induced Airway Epithelial Cell Cytotoxicity.

Objective: To investigate the effects of cigarette smoke (CS) on Serine/Threonine Kinase 11 (STK11) and to determine STK11's role in CS-induced airway epithelial cell cytotoxicity.Methods: STK11 expression levels in the lung tissues of smokers with or without COPD and mice exposed to CS or room air (RA) were determined by immunoblotting and RT-PCR. BEAS-2Bs-human bronchial airway epithelial cells were exposed to CS extract (CSE), and the changes in STK11 expression levels were determined by immunoblotting and RT-PCR. BEAS-2B cells were transfected with STK11-specific siRNA or STK11 expression plasmid, and the effects of CSE on airway epithelial cell cytotoxicity were measured. To determine the specific STK11 degradation-proteolytic pathway, BEAS-2Bs were treated with cycloheximide alone or combined with MG132 or leupeptin. Finally, to identify the F-box protein mediating the STK11 degradation, a screening assay was performed using transfection with a panel of FBXL E3 ligase subunits.Results: STK11 protein levels were significantly decreased in the lung tissues of smokers with COPD relative to smokers without COPD. STK11 protein levels were also significantly decreased in mouse lung tissues exposed to CS compared to RA. Exposure to CSE shortened the STK11 mRNA and protein half-life to 4 h in BEAS-2B cells. STK11 protein overexpression attenuated the CSE-induced cytotoxicity; in contrast, its knockdown augmented CSE-induced cytotoxicity. FBXL19 mediates CSE-induced STK11 protein degradation via the ubiquitin-proteasome pathway in cultured BEAS-2B cells. FBXL19 overexpression led to accelerated STK11 ubiquitination and degradation in a dose-dependent manner.Conclusions: Our results suggest that CSE enhances the degradation of STK11 protein in airway epithelial cells via the FBXL19-mediated ubiquitin-proteasomal pathway, leading to augmented cell death.HIGHLIGHTSLung tissues of COPD-smokers exhibited a decreased STK11 RNA and protein expression.STK11 overexpression attenuates CS-induced airway epithelial cell cytotoxicity.STK11 depletion augments CS-induced airway epithelial cell cytotoxicity.CS diminishes STK11 via FBXL19-mediated ubiquitin-proteasome degradation.

Breathing new life into the study of COPD with genes identified from genome-wide association studies.

COPD is a major cause of morbidity and mortality globally. While the significance of environmental exposures in disease pathogenesis is well established, the functional contribution of genetic factors has only in recent years drawn attention. Notably, many genes associated with COPD risk are also linked with lung function. Because reduced lung function precedes COPD onset, this association is consistent with the possibility that derangements leading to COPD could arise during lung development. In this review, we summarise the role of leading genes (HHIP, FAM13A, DSP, AGER and TGFB2) identified by genome-wide association studies in lung development and COPD. Because many COPD genome-wide association study genes are enriched in lung epithelial cells, we focus on the role of these genes in the lung epithelium in development, homeostasis and injury.

CircRNA-associated ceRNA networks (circCeNETs) in chronic obstructive pulmonary disease (COPD).

Chronic obstructive pulmonary disease (COPD), a chronic airway disorder, which is mostly brought on by cigarette smoke extract (CSE), is a leading cause of death which has a high frequency. In COPD patients, smoking cigarette could also trigger the epithelial-mesenchymal transition (EMT) of airway remodeling. One of the most significant elements of environmental contaminants that is linked to pulmonary damage is fine particulate matter (PM2.5). However, the basic processes of lung injury brought on by environmental contaminants and cigarette smoke are poorly understood, particularly the molecular pathways involved in inflammation. For the clinical management of COPD, investigating the molecular process and identifying workable biomarkers will be important. According to newly available research, circular RNAs (circRNAs) are aberrantly produced and serve as important regulators in the pathological processes of COPD. This class of non-coding RNAs (ncRNAs) functions as microRNA (miRNA) sponges to control the levels of gene expression, changing cellular phenotypes and advancing disease. These findings led us to concentrate our attention in this review on new studies about the regulatory mechanism and potential roles of circRNA-associated ceRNA networks (circCeNETs) in COPD.

Bioinformatics analysis of hypoxia associated genes and inflammatory cytokine profiling in COPD-PH.

Pulmonary hypertension (PH) in chronic obstructive pulmonary disease (COPD) is associated with worse clinical outcomes and decreased survival rates. In absence of disease specific diagnostic/therapeutic targets and unclear pathophysiology, there is an urgent need for the identification of potential genetic/molecular markers and disease associated pathways. The present study aims to use a bioinformatics approach to identify and validate hypoxia-associated gene signatures in COPD-PH patients. Additionally, hypoxia-related inflammatory profile is also explored in these patients. Microarray dataset obtained from the Gene Expression Omnibus repository was used to identify differentially expressed genes (DEGs) in a hypoxic PH mice model. The top three hub genes identified were further validated in COPD-PH patients, with chemokine (C-X-C motif) ligand 9 (CXCL9) and CXCL12 showing significant changes in comparison to healthy controls. Furthermore, multiplexed analysis of 10 inflammatory cytokines, tumor necrosis factor alpha (TNF-α), transforming growth factor ß (TGF-ß), interleukin 1-beta (IL-1ß), IL-4, IL-5, IL-6, IL-13, IL-17, IL-18 and IL-21 was also performed. These markers showed significant changes in COPD-PH patients as compared to controls. They also exhibited the ability to differentially diagnose COPD-PH patients in comparison to COPD. Additionally, IL-6 and IL-17 showed significant positive correlation with systolic pulmonary artery pressure (sPAP). This study is the first report to assess the levels of CXCL9 and CXCL12 in COPD-PH patients and also explores their link with the inflammatory profile of these patients. Our findings could be extended to better understand the underlying disease mechanism and possibly used for tailoring therapies exclusive for the disease.

Blood miRNAs as Potential Diagnostic Biomarkers for Chronic Obstructive Pulmonary Disease: A Meta-Analysis.

Purpose: Investigate the efficacy of blood microRNAs (miRNAs) as diagnostic biomarkers for Chronic Obstructive Pulmonary Disease (COPD). Patients and Methods: We conducted a comprehensive search in English and Chinese databases, selecting studies based on predetermined criteria. Diagnostic parameters like summarized sensitivity (SSEN), summarized specificity (SSPE), summarized positive likelihood ratio (SPLR), summarized negative likelihood ratio (SNLR), and diagnostic odds ratio (DOR), and area under the curve (AUC) of the summary receiver operating characteristic (SROC) curves were analyzed using a bivariate model. Each parameter was accompanied by a 95% confidence interval (CI). Results: Eighteen high-quality studies were included. For diagnosing COPD with blood miRNAs, the SSEN was 0.83 (95% CI 0.76-0.89), SSPE 0.76 (95% CI 0.70-0.82), SPLR 3.50 (95% CI 2.66-4.60), SNLR 0.22 (95% CI 0.15-0.33), DOR 15.72 (95% CI 8.58-28.77), and AUC 0.86 (95% CI 0.82-0.88). In acute exacerbations, SSEN was 0.85 (95% CI 0.76-0.91), SSPE 0.80 (95% CI 0.73-0.86), SPLR 4.26 (95% CI 3.05-5.95), SNLR 0.19 (95% CI 0.12-0.30), DOR 22.29 (95% CI 11.47-43.33), and AUC 0.89 (95% CI 0.86-0.91). Conclusion: Blood miRNAs demonstrate significant accuracy in diagnosing COPD, both in general and during acute exacerbations, suggesting their potential as reliable biomarkers.

The 3'UTR Polymorphisms in the NLRP3 Gene Associated with the Risk of COPD and Their Putative Effects on the microRNA Mechanism.

Aims: Evaluating the association between a single nucleotide polymorphism in the 3' untranslated region (3'UTR) of the miRNA binding site of the NLRP3 gene and the occurrence and development of chronic obstructive pulmonary disease (COPD) and providing information to aid in the early detection and treatment of COPD. Materials and Methods: The regulatory single nuclear polymorphisms (SNPs) located in NLRP3 3'UTR were searched by using the dbSNP database and miRNA binding site prediction database. Meanwhile, samples from COPD patients and healthy controls in the same period were used for verification. The clinical baseline information of all subjects was collected, and the transcription level and protein expression level of NLRP3 and the expression level of inflammatory factors downstream of NLRP3 were detected. The effects of SNPs' single nucleotide changes on the transcription and expression of inflammatory factors were analyzed. Results: The study included 418 participants (249 in the COPD group and 169 in the control group). NLRP3 SNPs with miRNA binding sites include rs10754558 (G > C), rs1664774076 (ATAT > del), and rs1664775106 (C > G). Furthermore, two genotypes, GCG and GCA, were discovered to have a linkage mutation at 3'UTR 459-461. COPD susceptibility is tightly associated with the expression of the rs1664774076 del/del genotype, and the risk of COPD increased by 2.770 times (p = 0.003). Type 459-461 GCA was substantially related to the likelihood of developing COPD at various stages (p < 0.05). Except for rs10754558, all homozygous mutants increased NLRP3 mRNA and protein levels. NLRP3 had the greatest area under the receiver operating characteristic (ROC) curve for predicting the development and diagnosis of COPD when compared with its downstream inflammatory variables (AUC = 0.9291). Conclusions: The NLRP3 rs1664774076 del/del genotype is a COPD susceptibility gene, and the GCA genotype at 459-461 can be used as an early predictor of COPD exacerbation. The NLRP3 3'UTR polymorphism may alter the loss of miRNA binding sites, leading to an increase in NLRP3 expression. In the development of COPD, NLRP3 has a better diagnostic value than traditional inflammatory factors. The Clinical Trials Registration number Z: protocol KY01-2020-11-06.