BackgroundChronic obstructive pulmonary disease (COPD) is a chronic lung inflammatory disease which has a close relationship with aging. Genome-wide analysis reveals that DNA methylation markers vary obviously with age. DNA methylation variations in peripheral blood have the potential to be biomarkers for COPD. However, the specific DNA methylation of aging-related genes in the peripheral blood of COPD patients remains largely unknown.MethodsFirstly, 9 aging-related differentially expressed genes (DEGs) in COPD patients were screened out from the 25 aging-related genes profile through a comprehensive screening strategy. Secondly, qPCR and multiple targeted bisulfite enrichment sequencing (MethTarget) were used to detect the mRNA level and DNA methylation level of the 9 differentially expressed genes in the peripheral blood of 60 control subjects and 45 COPD patients. The candidate functional CpG sites were selected on the basis of the regulation ability of the target gene expression. Thirdly, the correlation was evaluated between the DNA methylation level of the key CpG sites and the clinical parameters of COPD patients, including forced expiratory volume in one second (FEV1), forced expiratory volume in one second as percentage of predicted volume (FEV1%), forced expiratory volume/ forced vital capacity (FEV/FVC), modified British medical research council (mMRC) score, acute exacerbation frequency and the situation of frequent of acute aggravation (CAT) score. Lastly, differentially methylated CpG sites unrelated to smoking were also determined in COPD patients.ResultsOf the 9 differentially expressed aging-related genes, the mRNA expression of 8 genes were detected to be significantly down-regulated in COPD group, compared with control group. Meanwhile, the methylated level of all aging-related genes was changed in COPD group containing 219 COPD-related CpG sites in total. Notably, 27 CpG sites of FOXO3 gene showed a lower False Discovery Rate (FDR) and higher methylation difference values. Also, some variable DNA methylation is associated with the severity of COPD. Additionally, of the 219 COPD-related CpG sites, 147 CpG sites were not related to smoking.ConclusionThese results identified that the mRNA expression and DNA methylation level of aging-related genes were changed in male COPD patients, which provides a molecular link between aging and COPD. The identified CpG markers are associated with the severity of COPD and provide new insights into the prediction and identification of COPD.
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AbstractAirway epithelial cells (AECs) play a key role in asthma susceptibility and severity. Integrin β4 (ITGB4) is a structural adhesion molecule that is down-regulated in the airway epithelium of asthma patients. Although a few studies hint toward the role of ITGB4 in asthmatic inflammation pathogenesis, their specific resultant effects remain unexplored. In the present study, we determined the role of ITGB4 of AECs in the regulation of Th2 response and identified the underpinning molecular mechanisms. We found that ITGB4 deficiency led to exaggerated lung inflammation and AHR with higher production of CCL17 in house dust mite (HDM)-treated mice. ITGB4 regulated CCL17 production in AECs through EGFR, ERK and NF-κB pathways. EFGR-antagonist treatment or the neutralization of CCL17 both inhibited exaggerated pathological marks in HDM-challenged ITGB4-deficient mice. Together, these results demonstrated the involvement of ITGB4 deficiency in the development of Th2 responses of allergic asthma by down-regulation of EGFR and CCL17 pathway in AECs.
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