Background:Both dendritic cells (DCs) and nature cytotoxicity receptor-negative 3-type innate lymphoid cells (NCR-ILC3s) have been implicated in chronic lung inflammation in mice with cigarette smoke (CS)-induced chronic obstructive pulmonary disease (COPD). Our study aims to investigate whether erythromycin (EM) can suppress the differentiation of ILC3s into NCR-ILC3s through restraining DCs activation and therefore attenuate CS-related lung injuries in COPD mice. Methods:Our study comprised both in vivo and in vitro experiments. In the former, lung samples were collected from non-smokers, smokers, patients with stable COPD, as well as mice exposed to air, CS, and CS combined with EM, respectively. In the latter, lung DCs sifted by CD11c magnetic beads from mice exposed to either air or CS were co-cultured with lung CD45+Lin-CD127+ILCs sorted from air-exposed mice. EM was added to the co-culture involving DCs from CS-exposed mice. Flow cytometry and other assays were used to examine the quantities of NCR-ILC3s, DCs, relevant costimulatory molecules and cytokines in human tissues, mice lungs, and cell cultures. Results:Compared to non-smokers, lung NCR-ILC3s frequencies significantly increased in both smokers and COPD patients, and inversely correlated with forced expiratory volume in 1 second percent predicted (FEV1% pred) and diffusing capacity for carbon monoxide (P<0.05). CS-exposed mice showed evident emphysema and elevated frequencies of lung NCR-ILC3s and DCs. In contrast, mice receiving CS and EM displayed attenuated emphysema and reduced levels of NCR-ILC3s and DCs (P<0.05). In co-culture experiments, NCR-ILC3s frequencies were markedly higher when DCs were derived from CS-exposed mice than from air-exposed mice. This increase was substantially reversed by the addition of EM (P<0.05). Conclusions:Lung NCR-ILC3s frequencies escalate consistently in smokers, COPD patients, and CS-exposed mice. In CS-exposed mice, EM can inhibit DC-mediated NCR-ILC3s activation in the lungs, alleviate CS-related chronic lung inflammation, and ameliorate emphysema.

Objective: To explore the potential role of the RAGE/JAK/STAT pathway along with the activation of myeloid dendritic cells (mDCs) and B cells induced by cigarette smoke exposure in mice. Methods: 57BL/6J mice and RAGEfl/flCD11c-Cre mice were subjected to cigarette smoke for 24 weeks and mated with room air controls. Mice bone marrow-derived dendritic cells (BMDCs) were treated with cigarette smoke extracts (CSEs), CSE with the RAGE inhibitor FPS-ZM1 or CSE with the JAK2 inhibitor AG490. The extent of emphysema in these mice was assessed using the average alveolar lining distance (Lm). Real-time PCR was employed to quantify the mRNA expression levels of RAGE, JAK2, STAT1, STAT3 and STAT5 in lung tissue samples. The levels of IL-6 and IL-1β in mouse serum and BMDC supernatant were quantified using ELISA. Flow cytometry was employed to measure the expression of CD40, CD86, RAGE, p-JAK2, p-STAT1, p-STAT3 and p-STAT5 of lung mDCs and BMDCs in mice. Flow cytometry was employed to identify markers CD69, CD86 and CD138 on pulmonary B cells. Results: Exposing mice to cigarette smoke triggered an exaggerated pulmonary mDCs response and elevated the RAGE/JAK/STAT pathway in both pulmonary mDCs and lung tissue, correlating with enhanced B cells response in lungs. Conditional knockdown of RAGE on dendritic cells (DCs) resulted in a reduction of activity within JAK/STAT pathway, impeded the exaggerated mDCs and B cells responses induced by smoking, down-regulated the serum inflammatory response and mitigated emphysema in cigarette smoke-exposed mice. Within a regulated laboratory setting, BMDCs were activated, leading to the amplification of the RAGE/JAK/STAT pathway in these cells after CSE exposure. FPS-ZM1 and AG490 reduced inflammatory factors in the supernatant and activation of BMDC. Conclusion: In mice, prolonged exposure to cigarette smoke triggers the activation of mDCs by enhancing the RAGE/JAK/STAT pathway. Conditional knockdown of RAGE on DCs can prevent the activation of mDCs and B cells triggered by cigarette smoke, indicating that RAGE could be a potential target for treating smoking-induced emphysema.

The involvement of Group 3 innate lymphoid cells (ILC3s) and dendritic cells (DCs) in chronic lung inflammation has been increasingly regarded as the key to understand the inflammatory mechanisms of smoke-related chronic obstructive pulmonary disease (COPD). However, the mechanism underlying the engagement of both remains unclear. Our study aimed to explore NCR−ILC3 differentiation in the lungs of mice exposed to cigarette smoke (CS) and to further investigate whether DCs activated by CS exposure contribute to the differentiation of ILCs into NCR−ILC3s. The study involved both in vivo and in vitro experiments. In the former, the frequencies of lung NCR−ILC3s and NKp46−IL-17A+ ILCs and the expression of DCs, CD40, CD86, IL-23, and IL-1β quantified by flow cytometry were compared between CS-exposed mice and air-exposed mice. In the latter, NKp46−IL-17A+ ILC frequencies quantified by flow cytometry were compared after two cocultures, one involving lung CD45+Lin−CD127+ ILCs sorted from air-exposed mice and DCs sifted by CD11c magnetic beads from CS-exposed mice and another including identical CD45+Lin−CD127+ ILCs and DCs from air-exposed mice. The results indicated significant increases in the frequencies of NCR−ILC3s and NKp46−IL-17A+ ILCs; in the expression of DCs, CD40, CD86, IL-23, and IL-1β in CS-exposed mice; and in the frequency of NKp46−IL-17A+ ILCs after the coculture with DCs from CS-exposed mice. In conclusion, CS exposure increases the frequency of lung ILCs and NCR−ILC3s. CS-induced DC activation enhances the differentiation of ILCs into NCR−ILC3s, which likely acts as a mediating step in the involvement of NCR-ILC3s in chronic lung inflammation.

Objective Single-cell RNA sequencing (scRNA-Seq) and experimental verifies core genes of dendritic cells in chronic obstructive pulmonary disease (COPD). Methods scRNA-seq data GSE173896 and chip data GSE38974 were extracted from the Gene Expression Omnibus (GEO) database. GSE173896 was used to perform quality control, batch correction, dimensionality reduction clustering, cell type annotation and dendritic cell differentially expressed genes (DC-DEGs) identification. DEGs from the analysis of GSE38974 were intersected with DC-DEGs to obtain the common DC-DEGs. The diagnostic efficacy of the common DC-DEGs for COPD and their enrichment analysis were conducted. The correlation of the common DC-DEGs with activated dendritic cell (DCs), plasmacytoid dendritic cell (pDCs) and type 17 T helper(Th17) cells were analyzed. The mRNA expression level of the common DC-DEGs in the lung tissue of emphysema mice was verified. Results From GSE173896, 18 DC-DEGs were obtained between groups and from GSE38974, 646 DEGs were obtained. The intersection of the two resulted in 3 common DC-DEGs, including interleukin 1 receptor antagonist 1 (IL1RN), S100 calcicum-binding protein A8 (S100A8) and S100A9. Their respective area under curve (AUC) values were 0.841, 0.804 and 0.966. The GO and KEGG enrichment analysis mainly concentrated on chronic inflammatory response, collagen-containing extracellular matrix, receptor for advanced glycation end products (RAGE) binding, Toll-like receptor (TLR) binding and interleukin 17 (IL-17) signaling pathway. IL1RN, S100A8 and S100A9 were positively correlated with activated DCs, pDCs and Th17 cells. The results showed that the mRNA relative expression levels of IL1RN, S100A8 and S100A9 were up-regulated in the lung tissue of emphysema mice. Conclusion IL1RN, S100A8 and S100A9 may be the core genes of DCs in the pathogenesis of COPD, which potentially provide targets and a theoretical basis for subsequent COPD immunotherapy.

ObjectiveSystemic sclerosis (SSc) is a chronic autoimmune disease characterized by fibrosis. The challenge of early diagnosis, along with the lack of effective treatments for fibrosis, contribute to poor therapeutic outcomes and high mortality of SSc. Therefore, there is an urgent need to identify suitable biomarkers for early diagnosis of SSc.MethodsThree skin gene expression datasets of SSc patients and healthy controls were downloaded from Gene Expression Omnibus (GEO) database (GSE130955, GSE58095, and GSE181549). GSE130955 (48 early diffuse cutaneous SSc and 33 controls) were utilized to screen differentially expressed genes (DEGs) between SSc and normal skin samples. Least absolute shrinkage and selection operator (LASSO) regression and support vector machine recursive feature elimination (SVM-RFE) were performed to identify diagnostic genes and construct a diagnostic prediction model. The results were further validated in GSE58095 (61 SSc and 36 controls) and GSE181549 (113 SSc and 44 controls) datasets. Receiver operating characteristic (ROC) curves were applied for assessing the level of diagnostic ability. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to verify the diagnostic genes in skin tissues of out cohort (10 SSc and 5 controls). Immune infiltration analysis were performed using CIBERSORT algorithm.ResultsA total of 200 DEGs were identified between SSc and normal skin samples. Functional enrichment analysis revealed that these DEGs may be involved in the pathogenesis of SSc, such as extracellular matrix remodeling, cell-cell interactions, and metabolism. Subsequently, two critical genes (ENHO and NOX4) were identified by LASSO and SVM-RFE. ENHO was found down-regulated while NOX4 was up-regulated in skin of SSc patients and their expression levels were validated by above three datasets and our cohort. Notably, these differential expressions were more pronounced in patients with diffuse cutaneous SSc than in those with limited cutaneous SSc. Next, we developed a novel diagnostic model for SSc using ENHO and NOX4, which demonstrated strong predictive power in above three cohorts and in our own cohort. Furthermore, immune infiltration analysis revealed dysregulated levels of various immune cell subtypes within early SSc skin specimens, and a negative correlation was observed between the levels of ENHO and Macrophages M1 and M2, while a positive correlation was observed between the levels of NOX4 and Macrophages M1 and M2.ConclusionThis study identified ENHO and NOX4 as novel biomarkers that can be serve as a diagnostic prediction model for early detection of SSc and play a potential role in the pathogenesis of the disease.

T cells are one of the main cell types shaping the immune microenvironment in chronic obstructive pulmonary disease(COPD).They persist and play 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_cell data 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 of T 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,GSEA and KEGG enrichment analyses mainly identified genes involved in I-kappaB kinase/NF-kappaB signaling,receptor signaling pathway via STAT,regulation of CD4-positive cells,regulation of T-helper cell differentiation,chemokine signaling pathway,Toll-like receptor 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-genes of 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.

目的:利用生物信息学方法筛选并分析慢性阻塞性肺疾病(慢阻肺)与焦亡相关的关键基因.方法:首先对慢阻肺数据集GSE38974进行差异分析,得到差异基因后与焦亡相关基因取交集,最终获取焦亡相关的差异基因(DEprGs);对DEprGs进行GO和KEGG功能富集分析以及PPI分析;应用Cytoscape软件及其插件cytohubba的4种算法分析PPI的结果并取交集得出关键基因;用GSE38974、GSE47460数据集再次验证关键基因后筛选出最有意义的核心基因;12只C57BL/6小鼠分别于空气和烟草烟雾暴露24周后采用HE染色观察小鼠肺组织病理改变,并运用实时荧光定量聚合酶链式反应(RT-qPCR)在动物模型中验证最关键基因的差异性表达.结果:GSE38974与焦亡相关基因取交集共得到32个DEprGs,PPI进一步分析后得到7个关键基因;使用GSE38974及GSE47460两个数据集再次验证7个关键基因,在两个数据集中同时表达且有显著差异(P＜0.01)的核心基因仅有2个,即NAIP、HDAC6,其中NAIP上调,HDAC6下调;HE染色可见烟草烟雾暴露组(烟熏组)小鼠较空气暴露组(空气组)肺泡变薄且断裂融合,肺泡腔明显扩大,炎症细胞浸润明显,烟熏组小鼠平均肺泡间距明显大于空气组(P＜0.05);生物信息学分析的结果与核心基因实验验证结果一致,且相关性分析显示NAIP、HDAC6与小鼠的平均肺泡间距相关(P＜0.05).结论:在慢阻肺中,细胞焦亡相关基因NAIP高表达,可能参与慢阻肺的发生和发展;而HDAC6低表达,可能是潜在的保护因素.

目的:研究脂质代谢相关基因在慢性阻塞性肺疾病(COPD)中的表达,探讨脂质代谢关键基因在COPD中的可能机制.方法:从GEO和GeneCards数据库中获取数据,通过GO富集和PPI网络分析,筛选出差异表达的脂质代谢基因.香烟暴露24W建立肺气肿小鼠模型,HE染色观察小鼠肺组织病理学改变;使用实时荧光定量聚合酶链式反应(RT-qPCR)检测小鼠肺组织中脂质代谢关键基因的mRNA相对表达水平;用香烟烟雾提取物干预正常人来源的肺上皮细胞系BEAS-2B,通过细胞增殖实验(CCK-8)法测定香烟烟雾提取物干预浓度,RT-qPCR测定BEAS-2B细胞中脂质代谢关键基因的相对表达量.结果:基于GEO和GeneCards数据库,筛选出5个脂质代谢关键基因(PIK3CA、PRKAG2、GNB3、PLCB2、GLA),发现PIK3CA和PRK4G2基因在吸烟相关COPD中的小气道上皮细胞中高表达,而GNB3、PLCB2和GLA基因的表达下调.成功构建的肺气肿小鼠模型,与野生型对照组比较,小鼠肺组织中PIK3CA和PRKAG2基因的mRNA表达增加(P＜0.001),而GNB3、PLCB2和GLA基因的mRNA表达下调(P＜0.001),与香烟烟雾提取物干预的BEAS-2B细胞中基因表达情况一致.结论:脂质代谢关键基因PIK3CA、PRKAG2、GNB3、PLCB2、GLA参与了 COPD的发生发展,可能是识别吸烟相关COPD的潜在生物标志物.

Abstract Globally, chronic obstructive pulmonary disease(COPD) is the third leading cause of death. Necroptosis is a programmed regulated necrosis and contributes to the progression of lung disease. However, the function of necroptosis in COPD needs to be further elucidated. This study aimed to unravel the role of necroptosis in COPD via bioinformatics analysis and experimental validation. The GSE38974 and GSE8581 datasets were downloaded from the GEO database. Identified of differentially expressed genes(DEGs) from GSE38974. The GO, KEGG and GSEA enrichment analyses for DEGs.Differentially expressed genes of necroptosis(NR-DEGs) were obtained by combining DEGs and 159 necroptosis-related genes and the GO and KEGG were performed. The AUC values of NR-DEGs were assessed in the GSE38974 dataset and further were verified in the GSE8581 dataset. To further verify NR-DEGs in CSE-induced BEAS-2B cells by using RT-qPCR. The level of immune cell infiltration was quantified by ssGSEA analysis and the correlation analysis was performed between NR-DEGs and immune cell infiltration. We identified 646 DEGs and acquired 5 NR-DEGs(IL1B, IL-33, TNFAIP3, TNFRSF1A and CHMP4B) by combining 646 DEGs and 159 necroptosis-related genes. The GO, KEGG and GSEA enrichment analyses for the DEGs and NR-DEGs mainly involved in regulating of inflammatory response, cytokine-mediated signaling pathway, cytokine activity, receptor ligand activity and necroptosis. The AUC values of the NR-DEGs were 0.797, 0.971, 0.908, 1 and 1 from GSE38974 dataset and further were verified in the GSE8581 dataset were 0.741 and 0.737. The results of RT-qPCR showed that mRNA expression levels of IL1B and TNFAIP3 were up-regulated compared with control group(P<0.05). The analysis result of ssGSEA displayed that IL1B was significantly associated with Plasmacytoid.dendritic.cell, Activated.dendritic.cell, Macrophage, Central.memory.CD8.T.cell, Natural.killer.cell, Type.17.T.helper.cell, MDSC, and TNFAIP3 was significantly associated with Type.17.T.helper.cell, Natural.killer.cell, Macrophage, Central.memory.CD8.T.cell, Activated.dendritic.cell, Plasmacytoid.dendritic.cell, MDSC, Immature.B.cell, Gamma.delta.T.cell. According to the study, we found that necroptosis with COPD pathogenesis and immune cell infiltration is closely related, in particular, IL1B may through necroptosis-dependent pathway activate immune cell infiltration to promote the development of COPD, these may allow us to better understand the role of necroptosis in patients with COPD and provide better immunotherapeutic targets.

Interstitial lung disease (ILD) is a group of diffuse parenchymal infiltrating diseases of different etiologies. The neutrophil-to-lymphocyte ratio (NLR) can reflect ILD's existence, progression, and prognosis and is currently regarded as a promising biological marker. This meta-analysis assessed elevated NLR levels in ILD for their predictive value. From inception to July 27, 2022, the Scopus, Cochrane Library, Web of Science, Embase, and PubMed databases were checked thoroughly. We used the weighted mean difference (WMD) and 95% confidence interval (CI) to compare blood NLR values between groups. We examined the relationship between poor prognoses and elevated NLR concentrations in ILD patients using odds ratios (ORs) and 95% CI. After initially including 443 studies, 24 were ultimately analyzed. Fifteen studies(ILD:n = 2,912, Non-ILD: n = 2,868) revealed that the NLR values in the ILD group were relatively high (WMD = 0.61, 95% CI 0.43-0.79, p = 0.001). Eight articles (with poor prognoses: n = 407, without poor prognoses: n = 340) indicated that ILD patients with poor prognoses had higher NLR values (WMD = 1.33, 95% CI 0.32-2.33, p = 0.01). This distinction was especially noticeable in patients with the connective tissue disease (CTD)associated with ILD subgroup (WMD = 3.53, 95% CI 1.54-5.51, p = 0.0005). The pooled OR for increased NLR levels forecasting poor prognoses of ILD was 1.09 (95% CI 1.03-1.15, p = 0.0008). Increasing blood NLR values have clinical significance and application value for detecting ILD and predicting its poor prognosis, especially in CTD patients.

Abnormal lipid metabolism is known to increases the risk for metabolic diseases, such as type 2 diabetes mellitus(T2DM). The relationship between baseline ratio of triglyceride to HDL cholesterol (TG/HDL-C) and T2DM in Japanese adults was investigated in this study. Our secondary analysis included 8419 male and 7034 female Japanese subjects who were free of diabetes at baseline. The correlation between baseline TG/HDL-C and T2DM was analyzed by a proportional risk regression model, the nonlinear correlation between baseline TG/HDL-C and T2DM was analyzed by a generalized additive model (GAM), and the threshold effect analysis was performed by a segmented regression model. We conducted subgroup analyses in different populations. During the median 5.39 years follow-up, 373 participants, 286 males and 87 females, developed diabetes mellitus. After full adjustment for confounders, the baseline TG/HDL-C ratio positively correlated with the risk of diabetes (hazard ratio 1.19, 95% confidence interval 1.09–1.3), and smoothed curve fitting and two-stage linear regression analysis revealed a J-shaped relationship between baseline TG/HDL-C and T2DM. The inflection point for baseline TG/HDL-C was 0.35. baseline TG/HDL-C > 0.35 was positively associated with the development of T2DM (hazard ratio 1.2, 95% confidence interval 1.10–1.31). Subgroup analysis showed no significant differences in the effect between TG/HDL-C and T2DM in different populations. A J-shaped relationship was observed between baseline TG/HDL-C and T2DM risk in the Japanese population. When TG/HDL-C was higher than 0.35, there was a positive relationship between baseline TG/HDL-C and the incidence of diabetes mellitus.

We performed a meta-analysis to evaluate the effect of chronic obstructive pulmonary disease on surgical site wound infection, and other postoperative problems after coronary artery bypass grafting. A systematic literature search up to April 2022 was performed and 37 444 subjects with coronary artery bypass grafting at the baseline of the studies; 4320 of them were with the chronic obstructive pulmonary disease, and 33 124 were without chronic obstructive pulmonary disease. Odds ratio (OR), and mean difference (MD) with 95% confidence intervals (CIs) were calculated to assess the effect of chronic obstructive pulmonary disease on surgical site wound infection, and other postoperative problems after coronary artery bypass grafting using the dichotomous, and contentious methods with a random or fixed-effect model. The chronic obstructive pulmonary disease subjects had a significantly higher surgical site wound infection (OR, 1.27; 95% CI, 1.01-1.60, P = 0.04), respiratory failure (OR, 1.84; 95% CI, 1.55-2.18, P < 0.001), mortality (OR, 1.61; 95% CI, 1.37-1.89, P < 0.001), pneumonia (OR, 2.30; 95% CI, 1.97-2.68, P < 0.001), pleural effusion (OR, 1.78; 95% CI, 1.12-2.83, P = 0.02), stroke (OR, 1.99; 95% CI, 1.17-3.36, P = 0.01), and length of intensive care unit stay (MD, 0.73; 95% CI, 0.19-1.26, P = 0.008) after coronary artery bypass grafting compared with subjects without chronic obstructive pulmonary disease. However, chronic obstructive pulmonary disease subjects did not show any significant difference in length of hospital stay (MD, 0.83; 95% CI, -0.01 to 1.67, P = 0.05), and pneumothorax (OR, 1.59; 95% CI, 0.98-2.59, P = 0.06) after coronary artery bypass grafting compared with subjects without chronic obstructive pulmonary disease. The chronic obstructive pulmonary disease subjects had a significantly higher surgical site wound infection, respiratory failure, mortality, pneumonia, pleural effusion, stroke, and length of intensive care unit stay, and no significant difference in length of hospital stay, and pneumothorax after coronary artery bypass grafting compared with subjects without chronic obstructive pulmonary disease. The analysis of outcomes should be with caution because of the low sample size of 1 out of 11 studies in the meta-analysis and a low number of studies in certain comparisons.

Purpose:Smoking is recognized as a risk factor for Chronic Obstructive Pulmonary Disease (COPD), yet only 20-25% of smokers eventually develop COPD. Since its molecular pathogenesis remains unclear, there is an important need to further understand genetic differences between smokers with COPD and healthy smokers, screen out high-risk and susceptible groups among smokers, and find effective therapeutic targets.Methods:Bioinformatics tools were used to screen biomarkers that were significantly associated with COPD smokers and healthy smokers. qRT-PCR and Western blotting analysis were used to detect hub gene expression in CSE-treated BEAS-2B cells and lung tissue of COPD mouse models.Results:Our study identified 132 DEGs. The GO and KEGG analyses suggested that the ECM-receptor interaction, MAPK signaling pathway, Chemokine signaling pathway, PI3K-Akt signaling pathway, extracellular matrix organization and collagen fibril organization were associated with the occurrence and development of COPD. In addition, WGCNA analysis of GSE1650 showed that the brown module was most correlated with COPD. The intersection between the brown module and DEGs was used to identify 9 HUB genes (COL14A1, SULF1, MOXD1, CXCL12, CHRNA1, COMP, POU2AF1, MMP11, THBS2) that showed consistent expression and upregulation. Both the mRNA and protein expression levels of the Hub genes (except that of MMP11) were significantly upregulated in tobacco smoke exposed mouse emphysema models and CSE treated BEAS-2B cells.Conclusion:Our results suggest that COL14A1, SULF1, MOXD1, CXCL12, CHRNA1, COMP, POU2AF1, and THBS2 may be potentially useful biomarkers for identifying smokers with a risk of developing COPD. The GO and KEGG functional enrichment analyses further confirmed the significant role played by ECM in the pathogenesis of COPD. The results of this study may provide further insights into the pathogenetic mechanisms involved in COPD.

Smoking is a well-established risk factor for chronic obstructive pulmonary disease (COPD). Chronic lung inflammation continues even after smoking cessation and leads to COPD progression. To date, anti-inflammatory therapies are ineffective in improving pulmonary function and COPD symptoms, and new molecular targets are urgently needed to deal with this challenge. The receptor for advanced glycation end-products (RAGE) was shown to be relevant in COPD pathogenesis, since it is both a genetic determinant of low lung function and a determinant of COPD susceptibility. Moreover, RAGE is involved in the physiological response to cigarette smoke exposure. Since innate and acquired immunity plays an essential role in the development of chronic inflammation and emphysema in COPD, here we summarized the roles of RAGE and its ligand HMGB1 in COPD immunity.

目的 回顾性分析广西医科大学第一附属医院近15年来不同科室收治的气管支气管异物病例的临床特点,为气管支气管异物的诊治提供临床经验与参考.方法 收集并整理2005年1月-2019年12月就诊于耳鼻咽喉头颈外科、儿科、呼吸内科及其他科室诊断为气管支气管异物的病例资料.本研究每5年作为1个阶段,将所收集病例分为2005-2009年、2010-2014年、2015-2019年3个阶段,总结比较不同阶段、不同科室气管支气管异物病例的诊断治疗特点.结果 ①本研究共收集了 699例气管支气管异物病例,其中耳鼻咽喉头颈外科549例(78.5％),儿科70例(10％),呼吸内科65例(9.3％),其他科15例(2.1％).在第1个5年阶段中,患者以耳鼻咽喉头颈外科收治为主(90.1％);至2019年,儿科和呼吸内科收治患者比例增至56.1％,纤维支气管镜的应用比例由2012年的6.3％增至2019年的61％;②影像检查方式包括胸部X线253例(36.2％),胸部CT 404例(57.8％);胸部X线检出率为71.1％,胸部CT检出率为91.3％;③各科室15年总的平均住院日比较,其中耳鼻咽喉头颈外科3.68 d、儿科6.89 d、呼吸内科及其他科11.00 d;④手术相关并发症发生率为3.4％(24/699),其中耳鼻咽喉头颈外科为1.8％(10/549)、儿科8.6％(6/70)、呼吸内科10.8％(7/65)、其他科为6.7％(1/15);硬质支气管镜为2.0％(12/591)、纤维支气管镜为11.1％(12/108).结论 ①气管异物影像检查以胸部X片、CT为主,检出阳性率较高;②气管支气管异物主要收治科室为耳鼻咽喉头颈外科,儿科、呼吸内科近年来收治病例数增加.气管异物取出方式逐渐由硬性支气管镜转向纤维支气管软镜;③随着诊治经验增加,病种平均住院日有缩短趋势;④并发症发生率或与不同科室及手术操作经验有关.

Macrophages serve an active role in the pathophysiology of chronic obstructive pulmonary disease (COPD). Erythromycin (EM) has been verified as an effective treatment for COPD. However, there are few studies on the effect of EM on the ultrastructure of macrophages exposed to cigarette smoke extract (CSE). In the present study, human macrophages were randomly divided into three groups: The control, CSE and the CSE+EM group, using electron microscopy, the effect of EM was evaluated by comparing the ultrastructural changes between these groups. The macrophages were additionally divided into a further four groups: The control, CSE, CSE+EM 24 h and CSE+EM 48 h groups. The generation of reactive oxygen species (ROS) in each group was evaluated by detecting fluorescence intensity. It was observed that the cellular ultrastructure of the CSE group exhibited abnormal changes, though this effect was reversed back to the level of the control in the CSE+EM group. Compared with the control group, the ROS expression level was significantly increased in the CSE group (P < .05); however, compared with the CSE group, the ROS concentration was decreased in the CSE+EM 24 h (P < .05) and CSE+EM 48 h groups (P < .05), though this was more apparent in the EM 48 h group. It was concluded that EM protects human macrophages against CSE. Moreover, it was hypothesized that EM may reduce the symptoms of patients with COPD by protecting the macrophage ultrastructure from the effects of CSE, resulting in the decreased generation of ROS, inhibiting autophagy and reducing endoplasmic reticulum stress.

Objective. To explore the effect of combined treatment of PD-1 inhibitor and chemotherapy on the level of peripheral blood T lymphocytes in non-small-cell lung cancer (NSCLC) patients and its relationship with prognosis. Methods. Retrospective analysis was conducted on 150 NSCLC patients treated in Guangxi Medical University Affiliated Tumor Hospital from June 2018 to September 2020, including 77 patients treated with PD-1 inhibitor combined with chemotherapy as the observation group (OG) and 73 patients with chemotherapy alone as the control group (CG). Therapeutic efficacy, immune function indexes, serum tumor markers, incidence of adverse reactions during hospitalization, 1-year survival rate, and life quality after 6 months of treatment were observed and compared between two groups. Results. Compared to the CG, the therapeutic effect of OG was evidently better. Six months after treatment, levels of CD4+/CD8+, NK cells, and CD4 + in two groups were elevated markedly, and indexes of OG were notably and comparatively higher than those in the other group. After treatment, OG was observed with a marked decline regarding levels of CYFRA21-1, CEA, and CA125 compared to those in the CG; and there was no notable difference in terms of adverse reaction occurrence between two groups, but the 1-year survival rate and 6-month life quality in OG over ranked those in CG. Conclusion. For NSCLC patients, the PD-1 inhibitor given on the basis of chemotherapy can further improve the clinical efficacy and improve immune function and long-term survival rate of patients on the premise of ensuring the safety of treatment, which is worth promoting in clinical practice.

Abstract Background: Abnormal lipid metabolism is known to increases the risk for metabolic diseases, such as type 2 diabetes mellitus(T2DM). The relationship between baseline ratio of triglyceride to HDL cholesterol (TG/HDL-C) and T2DM in Japanese adults was investigated in this study.Methods: Our secondary analysis included 8419 male and 7034 female Japanese subjects who were free of diabetes at baseline. The correlation between baseline TG/HDL-C and T2DM was analyzed by a proportional risk regression model, the nonlinear correlation between baseline TG/HDL-C and T2DM was analyzed by a generalized additive model (GAM), and the threshold effect analysis was performed by a segmented regression model. We conducted subgroup analyses in different populationsResults: During the median 5.39 years follow-up, 373 participants, 286 males and 87 females, developed diabetes mellitus. After full adjustment for confounders, the baseline TG/HDL-C ratio positively correlated with the risk of diabetes (hazard ratio 1.19, 95% confidence interval 1.09-1.3), and smoothed curve fitting and two-stage linear regression analysis revealed a J-shaped relationship between baseline TG/HDL-C and T2DM. The inflection point for baseline TG/HDL-C was 0.35. baseline TG/HDL-C>0.35 was positively associated with the development of T2DM (hazard ratio 1.2, 95% confidence interval 1.10-1.31). Subgroup analysis showed no significant differences in the effect between TG/HDL-C and T2DM in different populations.Conclusion：A J-shaped relationship was observed between baseline TG/HDL-C and T2DM risk in the Japanese population. When TG/HDL-C was higher than 0.35, there was a positive relationship between baseline TG/HDL-C and the incidence of diabetes mellitus.

Objectives Present study aims to identify the essential mRNAs responsible for the development of brain neurovascular-related metastases (BNM) among lung adenocarcinoma (LUAD) patients. Further, we attempted to predict brain metastases more accurately and prevent their development in LUAD patients. Methods Transcriptome data analysis was used to identify differentially expressed mRNAs (DEMs) associated with brain metastasis, and thereby the ferroptosis index (FPI) is calculated using a computational model. Meanwhile, the DEmRNAs linked with FPI, and brain metastasis were derived by the intersection of these two groups of DEMs. We also constructed a ceRNA network containing these DEmRNAs, identifying the HCP5 /hsa-miR-17-5p/HOXA7 axis for analysis. Further, a clinical cohort was employed to validate the regulatory roles of molecules involved in the ceRNA regulatory axis. Results Here we report the development of a ceRNA network based on BNM-associated DEMs and FPI-associated DEmRNAs which includes three core miRNAs (hsa-miR-338-3p, hsa-miR-429, and hsa-miR-17-5p), three mRNAs (HOXA7, TBX5, and TCF21), and five lncRNAs (HCP5, LINC00460, TP53TG1). Using gene set enrichment analysis (GSEA) and survival analysis, the potential axis of HCP5 /hsa-miR-17-5p/HOXA7 was further investigated. It is found that HOXA7 and ferroptosis index are positively correlated while inhibiting tumor brain metastasis. It may be that HCP5 binds competitively with miR-17-5p and upregulates HOXA7 to increase iron death limiting brain cancer metastases Conclusions The expression of both HOXA7 and HCP5 is positively correlated with FPI, indicating a possible link between ferroptosis and BNM. According to the results of our study, the ferroptosis-related ceRNA HCP5 /hsa-miR-17-5p/HOXA7 axis may contribute to the development of BNM in LUAD patients.

目的:初步探讨红霉素(EM)对烟草烟雾提取物(CSE)诱导的人巨噬细胞炎症的抑制作用及其可能机制.方法:将体外培养的人单核细胞U937用佛波脂(PMA)诱导分化为人巨噬细胞.CCK-8法检测不同浓度、不同时间CSE及EM对细胞活性的影响.细胞分为对照组、CSE组(1％CSE刺激24 h或48 h)、CSE+EM组(1 μg/mL EM预孵育24 h或48 h后加1％CSE刺激24 h或48 h)、CSE+核因子(NF)-κB抑制剂吡咯烷二硫氨基甲酸(PDTC)组(20nmol/LPDTC预孵育24h或48h后加1％CSE刺激24h或48h)、Ⅰ型组蛋白去乙酰化酶(HDAC3)抑制剂曲古霉素(TSA)组(100ng/mLTSA孵育24h).采用酶联免疫吸附试验(ELISA)法检测细胞培养上清中炎症介质白介素(IL)-8浓度,应用凝胶迁移率阻滞实验(EMSA)检测NF-κB的活性,Western blotting法检测HDAC3和NF-κB蛋白表达.结果:与对照组比较,CSE组IL-8浓度、NF-κB转录活性明显增高,HDAC3蛋白表达下降(P＜0.05),TSA组HDAC3蛋白表达下降,NF-κB蛋白表达升高;与CSE组比较,CSE+EM组和CSE+PDTC组IL-8浓度、NF-κB转录活性及NF-κB蛋白表达明显下降,HDAC3蛋白表达升高(P＜0.05).结论:EM能够抑制CSE诱导的人巨噬细胞炎症介质IL-8释放,其抗炎活性可能与抑制NF-κB的转录活性和表达以及上调HDAC3表达有关.