{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T16:21:23Z","timestamp":1791908483077,"version":"4.3.4"},"reference-count":61,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,5,30]],"date-time":"2024-05-30T00:00:00Z","timestamp":1717027200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Chronic obstructive pulmonary disease (COPD) is one of the most prevalent chronic respiratory diseases and the fourth cause of mortality globally. Neutrophilic inflammation has a vital role in the occurrence and progression of COPD. This study aimed to identify the novel hub genes involved in neutrophilic inflammation in COPD through bioinformatic prediction and experimental validation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Both the single-cell RNA sequencing (scRNA-seq) dataset (GSE173896) and the RNA sequencing (RNA-seq) dataset (GSE57148) were downloaded from the Gene Expression Omnibus (GEO) database. The Seurat package was used for quality control, dimensions reduction, and cell identification of scRNA-seq. The irGSEA package was used for scoring individual cells. The Monocle2 package was used for the trajectory analysis of neutrophils. The CIBERSORT algorithm was used for analysis of immune cell infiltration in the lungs of COPD patients and controls in RNA-seq dataset, and weighted gene co-expression network analysis (WGCNA) correlated gene modules with neutrophil infiltration. The Mendelian randomization (MR) analysis explored the causal relationship between feature DEGs and COPD. The protein\u2013protein interaction (PPI) network of novel hub genes was constructed, and real-time quantitative polymerase chain reaction (qRT-PCR) was used to validate novel hub genes in clinical specimens.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In scRNA-seq, the gene sets upregulated in COPD samples were related to the neutrophilic inflammatory response and TNF-\u03b1 activation of the NF-\u03baB signaling pathway. In RNA-seq, immune infiltration analysis showed neutrophils were upregulated in COPD lung tissue. We combined data from differential and modular genes and identified 51 differential genes associated with neutrophilic inflammation. Using MR analysis, 6 genes were explored to be causally associated with COPD. Meanwhile, 11 hub genes were identified by PPI network analysis, and all of them were upregulated. qRT-PCR experiments validated 9 out of 11 genes in peripheral blood leukocytes of COPD patients. Furthermore, 5 genes negatively correlated with lung function in COPD patients. Finally, a network of transcription factors for NAMPT and PTGS2 was constructed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study identified nine novel hub genes related to the neutrophilic inflammation in COPD, and two genes were risk factors of COPD, which may serve as potential biomarkers for the clinical severity of COPD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2024.1410158","type":"journal-article","created":{"date-parts":[[2024,5,30]],"date-time":"2024-05-30T03:44:09Z","timestamp":1717040649000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":48,"title":["Identification of novel biomarkers related to neutrophilic inflammation in COPD"],"prefix":"10.3389","volume":"15","author":[{"given":"Yuchen","family":"Huang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Niu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuezhao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaochen","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanzhou","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiansheng","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,5,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201203-0505UP","article-title":"Update in chronic obstructive pulmonary disease 2011","volume":"185","author":"Agust\u00ed","year":"2012","journal-title":"Am J Respir Crit Care Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra0804752","article-title":"Immunologic aspects of chronic obstructive pulmonary disease","volume":"360","author":"Cosio","year":"2009","journal-title":"N Engl J Med"},{"key":"B3","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1183\/09031936.06.00025805","article-title":"Chronic obstructive pulmonary disease: current burden and future projections","volume":"27","author":"Lopez","year":"2006","journal-title":"Eur Respir J"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1136\/bmj-2021\u2013069679","article-title":"Burden of chronic obstructive pulmonary disease and its attributable risk factors in 204 countries and territories, 1990\u20132019: results from the Global Burden of Disease Study 2019","volume":"378","author":"Safiri","year":"2022","journal-title":"BMJ"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1007\/978\u20131-0716\u20130904-0_16","article-title":"Airway inflammation biomarker for precise management of neutrophil-predominant COPD","volume":"2204","author":"Liang","year":"2020","journal-title":"Methods Mol Biol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1080\/15412555.2018.1476475","article-title":"Neutrophilic inflammation in the pathogenesis of chronic obstructive pulmonary disease","volume":"15","author":"Butler","year":"2018","journal-title":"COPD"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.2147\/COPD.S366126","article-title":"Pathological mechanism and targeted drugs of COPD","volume":"17","author":"Guo","year":"2022","journal-title":"Int J Chron Obstruct Pulmon Dis"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.00784\u20132015","article-title":"Sputum inflammatory cells in COPD patients classified according to GOLD 2011 guidelines","volume":"47","author":"Bartoli","year":"2016","journal-title":"Eur Respir J"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.112525","article-title":"Systemic alterations in neutrophils and their precursors in early-stage chronic obstructive pulmonary disease","volume":"42","author":"Kapellos","year":"2023","journal-title":"Cell Rep"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2016010098","article-title":"Mendelian randomization as an approach to assess causality using observational data","volume":"27","author":"Sekula","year":"2016","journal-title":"J Am Soc Nephrol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.04.048","article-title":"Integrated analysis of multimodal single-cell data","volume":"184","author":"Hao","year":"2021","journal-title":"Cell"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.4314","article-title":"Dimensionality reduction for visualizing single-cell data using UMAP","volume":"37","author":"Becht","year":"2018","journal-title":"Nat Biotechnol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4402","article-title":"Reversed graph embedding resolves complex single-cell trajectories","volume":"14","author":"Qiu","year":"2017","journal-title":"Nat Methods"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3337","article-title":"Robust enumeration of cell subsets from tissue expression profiles","volume":"12","author":"Newman","year":"2015","journal-title":"Nat Methods"},{"key":"B15","doi-asserted-by":"publisher","first-page":"Article17","DOI":"10.2202\/1544-6115.1128","article-title":"A general framework for weighted gene co-expression network analysis","volume":"4","author":"Zhang","year":"2005","journal-title":"Stat Appl Genet Mol Biol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: an R package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"OMICS"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/s41588\u2013021-00913-z","article-title":"Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression","volume":"53","author":"V\u00f5sa","year":"2021","journal-title":"Nat Genet"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1101\/2020.08.10.244293","article-title":"The MRC IEU OpenGWAS data infrastructure","author":"Elsworth","year":"2020","journal-title":"bioRxiv"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.327.7414.557","article-title":"Measuring inconsistency in meta-analyses","volume":"327","author":"Higgins","year":"2003","journal-title":"BMJ"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1007\/s10654-017-0255-x","article-title":"Interpreting findings from Mendelian randomization using the MR-Egger method","volume":"32","author":"Burgess","year":"2017","journal-title":"Eur J Epidemiol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa1074","article-title":"The STRING database in 2021: customizable protein-protein networks, and functional characterization of user-uploaded gene\/measurement sets","volume":"49","author":"Szklarczyk","year":"2021","journal-title":"Nucleic Acids Res"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz1001","article-title":"JASPAR 2020: update of the open-access database of transcription factor binding profiles","volume":"48","author":"Fornes","year":"2020","journal-title":"Nucleic Acids Res"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz240","article-title":"NetworkAnalyst 3.0: a visual analytics platform for comprehensive gene expression profiling and meta-analysis","volume":"47","author":"Zhou","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"B24","doi-asserted-by":"publisher","first-page":"17363","DOI":"10.3390\/ijms242417363","article-title":"Therapeutic targets and precision medicine in COPD: Inflammation, ion channels, both, or neither","volume":"24","author":"Bolger","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00047","article-title":"NETopathic inflammation in chronic obstructive pulmonary disease and severe asthma","volume":"10","author":"Uddin","year":"2019","journal-title":"Front Immunol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1586\/1744666X.2013.851347","article-title":"Neutrophils and emerging targets for treatment in chronic obstructive pulmonary disease","volume":"9","author":"Meijer","year":"2013","journal-title":"Expert Rev Clin Immunol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.jaci.2016.05.011","article-title":"Inflammatory mechanisms in patients with chronic obstructive pulmonary disease","volume":"138","author":"Barnes","year":"2016","journal-title":"J Allergy Clin Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1080\/13543776.2019.1672661","article-title":"MCL-1 inhibitors - where are we now (2019)","volume":"29","author":"Fletcher","year":"2019","journal-title":"Expert Opin Ther Pat"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1186\/1746\u20131596-7\u201365","article-title":"Delayed apoptosis by neutrophils from COPD patients is associated with altered Bak, Bcl-xl, and Mcl-1 mRNA expression","volume":"7","author":"Zhang","year":"2012","journal-title":"Diagn Pathol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2010.03.003","article-title":"Mature human neutrophils constitutively express the transcription factor EGR-1","volume":"47","author":"Cullen","year":"2010","journal-title":"Mol Immunol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00413.2022","article-title":"Role of early growth response 1 in inflammation-associated lung diseases","volume":"325","author":"Zou","year":"2023","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00158110","article-title":"Role of IL-1\u03b1 and the Nlrp3\/caspase-1\/IL-1\u03b2 axis in cigarette smoke-induced pulmonary inflammation and COPD","volume":"38","author":"Pauwels","year":"2011","journal-title":"Eur Respir J"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.2147\/COPD.S131877","article-title":"Serum IL-1\u03b2 and IL-17 levels in patients with COPD: associations with clinical parameters","volume":"12","author":"Zou","year":"2017","journal-title":"Int J Chron Obstruct Pulmon Dis"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2018.09.018","article-title":"Distinct compartmentalization of the chemokines CXCL1 and CXCL2 and the atypical receptor ACKR1 determine discrete stages of neutrophil diapedesis","volume":"49","author":"Girbl","year":"2018","journal-title":"Immunity"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00290.2015","article-title":"p53- and PAI-1-mediated induction of C-X-C chemokines and CXCR2: importance in pulmonary inflammation due to cigarette smoke exposure","volume":"310","author":"Tiwari","year":"2016","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00039.2005","article-title":"Role of CXCR2 in cigarette smoke-induced lung inflammation","volume":"289","author":"Thatcher","year":"2005","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2009.05.018","article-title":"Regulation of superoxide dismutase genes: implications in disease","volume":"47","author":"Miao","year":"2009","journal-title":"Free Radic Biol Med"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1155\/2020\/7582980","article-title":"Sirtuin 3 inhibits airway epithelial mitochondrial oxidative stress in cigarette smoke-induced COPD","volume":"2020","author":"Zhang","year":"2020","journal-title":"Oxid Med Cell Longev"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2004.08.008","article-title":"Particulate phase cigarette smoke increases MnSOD, NQO1, and CINC-1 in rat lungs","volume":"37","author":"Stringer","year":"2004","journal-title":"Free Radic Biol Med"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1172\/JCI80631","article-title":"The RNA-binding protein tristetraprolin schedules apoptosis of pathogen-engaged neutrophils during bacterial infection","volume":"127","author":"Ebner","year":"2017","journal-title":"J Clin Invest"},{"key":"B41","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1080\/15412555.2018.1535581","article-title":"Monitoring antioxidant enzyme activity during exacerbations of chronic obstructive pulmonary disease","volume":"15","author":"Antus","year":"2018","journal-title":"COPD"},{"key":"B42","doi-asserted-by":"publisher","first-page":"843","DOI":"10.3390\/ijms22020843","article-title":"The effect of hypoxia on the expression of CXC chemokines and CXC chemokine receptors-A review of literature","volume":"22","author":"Korbecki","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B43","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/j.cellsig.2018.11.004","article-title":"How do chemokines navigate neutrophils to the target site: Dissecting the structural mechanisms and signaling pathways","volume":"54","author":"Rajarathnam","year":"2019","journal-title":"Cell Signal"},{"key":"B44","doi-asserted-by":"publisher","first-page":"3733","DOI":"10.3390\/cells11233733","article-title":"Single-cell sequencing reveals the regulatory role of maresin1 on neutrophils during septic lung injury","volume":"11","author":"Wang","year":"2022","journal-title":"Cells"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.2174\/15680266113136660208","article-title":"Nicotinamide phosphoribosyltransferase as a target in inflammation- related disorders","volume":"13","author":"Montecucco","year":"2013","journal-title":"Curr Top Med Chem"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1007\/978\u20133-642\u201317214-4_7","article-title":"Nampt and its potential role in inflammation and type 2 diabetes","volume":"203","author":"Garten","year":"2011","journal-title":"Handb Exp Pharmacol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.00358","article-title":"Two metabolic enzymes with key roles in inflammation","volume":"10","author":"Audrito","year":"2020","journal-title":"Front Oncol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1038\/nm.1913","article-title":"NAMPT is essential for the G-CSF-induced myeloid differentiation via a NAD(+)-sirtuin-1-dependent pathway","volume":"15","author":"Skokowa","year":"2009","journal-title":"Nat Med"},{"key":"B49","doi-asserted-by":"publisher","first-page":"5584","DOI":"10.3390\/ijms20225584","article-title":"Neutrophil maturation and survival is controlled by IFN-dependent regulation of NAMPT signaling","volume":"20","author":"Siakaeva","year":"2019","journal-title":"Int J Mol Sci"},{"key":"B50","doi-asserted-by":"publisher","first-page":"e002875","DOI":"10.1136\/jitc-2021\u2013002875","article-title":"Aged neutrophils form mitochondria-dependent vital NETs to promote breast cancer lung metastasis","volume":"9","author":"Yang","year":"2021","journal-title":"J Immunother Cancer"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200419930","article-title":"Pre-B cell colony-enhancing factor inhibits neutrophil apoptosis in experimental inflammation and clinical sepsis","volume":"113","author":"Jia","year":"2004","journal-title":"J Clin Invest"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2011.4487","article-title":"Inhibition of nicotinamide phosphoribosyltransferase reduces neutrophil-mediated injury in myocardial infarction","volume":"18","author":"Montecucco","year":"2013","journal-title":"Antioxid Redox Signal"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1111\/1348\u20130421.12885","article-title":"Nicotinamide phosphoribosyltransferase inhibitor is a novel therapeutic candidate in LPS-induced neutrophil extracellular traps","volume":"65","author":"Ding","year":"2021","journal-title":"Microbiol Immunol"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.86492","article-title":"The PTGS2\/COX2-PGE2 signaling cascade in inflammation: Pro or anti","volume":"19","author":"Mart\u00edn-V\u00e1zquez","year":"2023","journal-title":"A Case study type 1 Diabetes mellitus. Int J Biol Sci"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.2174\/0929867325666180514112124","article-title":"Cyclooxygenase-2 inhibitors as a therapeutic target in inflammatory diseases","volume":"26","author":"Ferrer","year":"2019","journal-title":"Curr Med Chem"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.90593.2008","article-title":"Chronic obstructive pulmonary disease and neutrophil infiltration: role of cigarette smoke and cyclooxygenase products","volume":"298","author":"Profita","year":"2010","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1016\/j.pupt.2020.101896","article-title":"Effect of piperlongumine during exposure to cigarette smoke reduces inflammation and lung injury","volume":"61","author":"Sant'Ana","year":"2020","journal-title":"Pulm Pharmacol Ther"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1177\/1933719109348252","article-title":"Neutrophil infiltration and systemic vascular inflammation in obese women","volume":"17","author":"Shah","year":"2010","journal-title":"Reprod Sci"},{"key":"B59","doi-asserted-by":"publisher","first-page":"3759","DOI":"10.1038\/s41598\u2013017-03696\u20138","article-title":"Sex differences in prostaglandin biosynthesis in neutrophils during acute inflammation","volume":"7","author":"Pace","year":"2017","journal-title":"Sci Rep"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1007\/s10753\u2013022-01690\u20135","article-title":"Neutrophil-Derived COX-2 has a Key Role during Inflammatory Hyperalgesia","volume":"45","author":"Carvalho","year":"2022","journal-title":"Inflammation"},{"key":"B61","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.mehy.2016.05.004","article-title":"Is osseointegration inflammation-triggered","volume":"93","author":"Vitkov","year":"2016","journal-title":"Med Hypotheses"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1410158\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,30]],"date-time":"2024-05-30T03:44:27Z","timestamp":1717040667000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1410158\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,30]]},"references-count":61,"alternative-id":["10.3389\/fimmu.2024.1410158"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2024.1410158","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,30]]},"article-number":"1410158"}}