{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:16:05Z","timestamp":1785424565151,"version":"3.56.0"},"reference-count":68,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T00:00:00Z","timestamp":1761782400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100022294","name":"National Taiwan University Hospital Yunlin Branch","doi-asserted-by":"crossref","award":["NTUHYL107.S007"],"award-info":[{"award-number":["NTUHYL107.S007"]}],"id":[{"id":"10.13039\/501100022294","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation associated with enhanced chronic airway inflammation. Growth factors implicated in COPD\u2019s inflammatory processes may serve as biomarkers for disease progression and exacerbation risk. This study evaluated the relationship between serum growth factors and COPD exacerbations over one year. Serum levels of eleven growth factors, including brain-derived neurotrophic factor (BDNF), leukemia inhibitory factor (LIF), fibroblast growth factor-2 (FGF-2), vascular endothelial growth factor (VEGF), nerve growth factor (NGF), epidermal growth factor (EGF), and stem cell factor (SCF), were measured in COPD patients at baseline. Participants were followed prospectively for one year, and associations between these biomarkers and acute exacerbations (AE) and frequent acute exacerbations (Frequent AE) were assessed using statistical analyses and receiver operating characteristic (ROC) curves. Among the study population, 42 patients experienced at least one AE within the follow-up period. Lower serum FGF-2 levels were significantly associated with increased AE risk (adjusted odds ratio significant after covariate adjustment). ROC analysis identified FGF-2 \u2264 9.12 pg\/mL as a predictor of AE (AUC = 0.614, sensitivity = 64.3%, specificity = 57.1%, p = 0.032). For Frequent AE, eight patients experienced multiple exacerbations and exhibited significantly lower levels of NGF, EGF, FGF-2, and LIF. After adjustment, NGF remained significantly predictive; NGF \u2264 25.23 pg\/mL demonstrated strong discriminatory power for Frequent AE (AUC = 0.797, p &lt; 0.001). However, interpretations are limited by the small Frequent AE subgroup. Serum growth factors, particularly FGF-2 and NGF, are associated with COPD exacerbation risk. Lower serum FGF-2 may indicate a higher likelihood of acute exacerbations, while lower NGF strongly predicts frequent exacerbations. Larger studies and longer follow-ups are needed to confirm these biomarkers\u2019 predictive utility.<\/jats:p>","DOI":"10.3390\/ijms262110584","type":"journal-article","created":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T01:23:59Z","timestamp":1761873839000},"page":"10584","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Association Between Serum Growth Factors and Risk of Acute Exacerbation in Chronic Obstructive Pulmonary Disease: A One-Year Prospective Study"],"prefix":"10.3390","volume":"26","author":[{"given":"Hong-Yih","family":"Tien","sequence":"first","affiliation":[{"name":"Department of Emergency Medicine, National Taiwan University Hospital Yunlin Branch, Douliou City 640204, Yunlin County, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9002-7255","authenticated-orcid":false,"given":"Chung-Yu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, Douliou City 640204, Yunlin County, Taiwan"},{"name":"College of Medicine, National Taiwan University, Taipei 100225, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chong-Jen","family":"Yu","sequence":"additional","affiliation":[{"name":"College of Medicine, National Taiwan University, Taipei 100225, Taiwan"},{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, National Taiwan University Hospital, Taipei 100225, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao-Chien","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Medicine, National Taiwan University, Taipei 100225, Taiwan"},{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, National Taiwan University Hospital, Taipei 100225, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s12931-024-03051-2","article-title":"Global, regional, and national burden of chronic obstructive pulmonary disease and its attributable risk factors from 1990 to 2021: An analysis for the Global Burden of Disease Study 2021","volume":"26","author":"Wang","year":"2025","journal-title":"Respir. Res."},{"key":"ref_2","unstructured":"Global Initiative for Chronic Obstructive Lung Disease (GOLD) (2025, October 26). Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease (2025 Report). Available online: https:\/\/goldcopd.org\/2025-gold-report\/."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1001\/jama.1994.03520190043033","article-title":"Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1. The Lung Health Study","volume":"272","author":"Anthonisen","year":"1994","journal-title":"JAMA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1183\/09031936.00146905","article-title":"Clinical relevance of airway remodelling in airway diseases","volume":"30","author":"James","year":"2007","journal-title":"Eur. Respir. J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1513\/pats.200907-079DP","article-title":"What drives the peripheral lung-remodeling process in chronic obstructive pulmonary disease?","volume":"6","author":"Hogg","year":"2009","journal-title":"Proc. Am. Thorac. Soc."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1080\/15412555.2018.1444022","article-title":"COPD 2017: A Year in Review","volume":"15","author":"Crisafulli","year":"2018","journal-title":"COPD J. Chronic Obstr. Pulm. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1600791","DOI":"10.1183\/13993003.00791-2016","article-title":"Management of COPD exacerbations: A European Respiratory Society\/American Thoracic Society guideline","volume":"49","author":"Wedzicha","year":"2017","journal-title":"Eur. Respir. J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1186\/1465-9921-7-74","article-title":"Markers of exacerbation severity in chronic obstructive pulmonary disease","volume":"7","author":"Franciosi","year":"2006","journal-title":"Respir. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1186\/s12931-014-0147-5","article-title":"Surfactant protein D, Club cell protein 16, Pulmonary and activation-regulated chemokine, C-reactive protein, and Fibrinogen biomarker variation in chronic obstructive lung disease","volume":"15","author":"Vestbo","year":"2014","journal-title":"Respir. Res."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Hoult, G., Gillespie, D., Wilkinson, T.M.A., Thomas, M., and Francis, N.A. (2022). Biomarkers to guide the use of antibiotics for acute exacerbations of COPD (AECOPD): A systematic review and meta-analysis. BMC Pulm. Med., 22.","DOI":"10.1186\/s12890-022-01958-4"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Su, H., Li, F., and Li, J. (2025). The analysis of risk factors associated with readmission in patients with exacerbation of COPD. Medicine, 104.","DOI":"10.1097\/MD.0000000000041997"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1186\/s12931-022-02158-8","article-title":"Relationships of serum CC16 levels with smoking status and lung function in COPD","volume":"23","author":"Gribben","year":"2022","journal-title":"Respir. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2645","DOI":"10.1056\/NEJMoa032158","article-title":"The nature of small-airway obstruction in chronic obstructive pulmonary disease","volume":"350","author":"Hogg","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1016\/j.rmed.2007.01.003","article-title":"Platelet and plasma BDNF in lower respiratory tract infections of the adult","volume":"101","author":"Lommatzsch","year":"2007","journal-title":"Respir. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1111\/j.1582-4934.2011.01356.x","article-title":"Brain-derived neurotrophic factor induces proliferation of human airway smooth muscle cells","volume":"16","author":"Aravamudan","year":"2012","journal-title":"J. Cell Mol. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.2174\/1570159X16666180412092859","article-title":"Nerve Growth Factor: Early Studies and Recent Clinical Trials","volume":"16","author":"Rocco","year":"2018","journal-title":"Curr. Neuropharmacol."},{"key":"ref_17","first-page":"601","article-title":"The expressions of nerve growth factor and its tyrosine kinase A receptor on alveolar macrophages in a rat model of chronic obstructive pulmonary disease","volume":"35","author":"Li","year":"2012","journal-title":"Zhonghua Jie He He Hu Xi Za Zhi"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1097\/ACI.0b013e328334f5de","article-title":"The role of neurotrophins in the pathophysiology of allergic rhinitis","volume":"10","author":"Raap","year":"2010","journal-title":"Curr. Opin. Allergy Clin. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"7709","DOI":"10.1016\/S0021-9258(19)38983-5","article-title":"Epidermal growth factor","volume":"265","author":"Carpenter","year":"1990","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.1096\/fasebj.14.10.1362","article-title":"Involvement of the epidermal growth factor receptor in epithelial repair in asthma","volume":"14","author":"Puddicombe","year":"2000","journal-title":"FASEB J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.4049\/jimmunol.164.3.1546","article-title":"Oxidative stress causes mucin synthesis via transactivation of epidermal growth factor receptor: Role of neutrophils","volume":"164","author":"Takeyama","year":"2000","journal-title":"J. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2867","DOI":"10.1002\/j.1460-2075.1991.tb07836.x","article-title":"Scatter factor and hepatocyte growth factor are indistinguishable ligands for the MET receptor","volume":"10","author":"Naldini","year":"1991","journal-title":"EMBO J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1242\/dev.125.7.1315","article-title":"Hepatocyte growth factor (HGF) acts as a mesenchyme-derived morphogenic factor during fetal lung development","volume":"125","author":"Ohmichi","year":"1998","journal-title":"Development"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"L641","DOI":"10.1152\/ajplung.00249.2004","article-title":"Defect of hepatocyte growth factor production by fibroblasts in human pulmonary emphysema","volume":"288","author":"Plantier","year":"2005","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1038\/nature05993","article-title":"p53 regulates maternal reproduction through LIF","volume":"450","author":"Hu","year":"2007","journal-title":"Nature"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1165\/ajrcmb.20.4.3429","article-title":"Leukemia inhibitory factor (LIF) and LIF receptor in human lung. Distribution and regulation of LIF release","volume":"20","author":"Knight","year":"1999","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1159\/000007022","article-title":"Serial changes in serum VEGF and HGF in patients with acute myocardial infarction","volume":"93","author":"Soeki","year":"2000","journal-title":"Cardiology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0304-419X(89)90031-0","article-title":"Structure and function of platelet-derived growth factor (PDGF) and related proteins","volume":"989","author":"Hannink","year":"1989","journal-title":"Biochim. Et Biophys. Acta (BBA)-Rev. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1111\/j.1398-9995.1995.tb02493.x","article-title":"Platelet-derived growth factor in asthma","volume":"50","author":"Chanez","year":"1995","journal-title":"Allergy"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1165\/rcmb.2014-0294TR","article-title":"Platelet-Derived Growth Factor Signaling in the Lung. From Lung Development and Disease to Clinical Studies","volume":"52","author":"Eickelberg","year":"2015","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4047","DOI":"10.1242\/dev.152587","article-title":"Fibroblast growth factors: Key players in regeneration and tissue repair","volume":"144","author":"Maddaluno","year":"2017","journal-title":"Development"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1007\/s00441-003-0756-7","article-title":"Fibroblast growth factors and their receptors in the central nervous system","volume":"313","author":"Reuss","year":"2003","journal-title":"Cell Tissue Res."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Tan, Y., Qiao, Y., Chen, Z., Liu, J., Guo, Y., Tran, T., Tan, K.S., Wang, D.-Y., and Yan, Y. (2020). FGF2, an Immunomodulatory Factor in Asthma and Chronic Obstructive Pulmonary Disease (COPD). Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.00223"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1007\/s003359900003","article-title":"The placenta growth factor gene of the mouse","volume":"7","author":"DiPalma","year":"1996","journal-title":"Mamm. Genome"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1136\/thx.2007.087155","article-title":"Increased expression of placenta growth factor in COPD","volume":"63","author":"Cheng","year":"2008","journal-title":"Thorax"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1111\/j.1365-2222.2006.02431.x","article-title":"Effect of glucocorticoids on stem cell factor (SCF) expression in human asthmatic bronchi","volume":"36","author":"Laval","year":"2006","journal-title":"Clin. Exp. Allergy"},{"key":"ref_37","first-page":"5","article-title":"Asthma: A dynamic disease of inflammation and repair","volume":"206","author":"Holgate","year":"1997","journal-title":"Ciba Found. Symp."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1038\/s41392-020-00222-7","article-title":"FGF\/FGFR signaling in health and disease","volume":"5","author":"Xie","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Baran, K., Skrzynska, K., Czyrek, A.A., Wittek, A., Krowarsch, D., Szlachcic, A., Zakrzewska, M., and Chudzian, J. (2025). Fibroblast Growth Factors in Lung Development and Regeneration: Mechanisms and Therapeutic Potential. Cells, 14.","DOI":"10.3390\/cells14161256"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.cytogfr.2021.09.002","article-title":"FGF\/FGFR signaling: From lung development to respiratory diseases","volume":"62","author":"Yang","year":"2021","journal-title":"Cytokine Growth Factor. Rev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1164\/ajrccm.150.1.7912988","article-title":"Cell proliferation in the bronchial mucosa of asthmatics and chronic bronchitics","volume":"150","author":"Demoly","year":"1994","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1002\/dvdy.24468","article-title":"Therapeutic and Pathological Roles of Fibroblast Growth Factors in Pulmonary Diseases","volume":"246","author":"Seeger","year":"2017","journal-title":"Dev. Dyn."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"218142","DOI":"10.4061\/2010\/218142","article-title":"Fibroblast growth factors: Biology, function, and application for tissue regeneration","volume":"2010","author":"Yun","year":"2010","journal-title":"J. Tissue Eng."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1089\/jir.2011.0079","article-title":"The Fibroblast Growth Factor Pathway and Its Role in the Pathogenesis of Lung Disease","volume":"32","author":"Dosanjh","year":"2012","journal-title":"J. Interferon Cytokine Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1038\/s12276-018-0178-y","article-title":"The role of FGF-2 in smoke- induced emphysema and the therapeutic potential of recombinant FGF-2 in patients with COPD","volume":"50","author":"Kim","year":"2018","journal-title":"Exp. Mol. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/S1357-2725(99)00123-5","article-title":"Fibroblast growth factor-2","volume":"32","author":"Nugent","year":"2000","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1038\/nrc2780","article-title":"Fibroblast growth factor signalling: From development to cancer","volume":"10","author":"Turner","year":"2010","journal-title":"Nat. Rev. Cancer"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1165\/ajrcmb.20.5.3288","article-title":"Acidic fibroblast growth factor induces an antifibrogenic phenotype in human lung fibroblasts","volume":"20","author":"Becerril","year":"1999","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1002\/path.1748","article-title":"Chronic obstructive pulmonary disease is associated with enhanced bronchial expression of FGF-1, FGF-2, and FGFR-1","volume":"206","author":"Kranenburg","year":"2005","journal-title":"J. Pathol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1136\/thx.2002.002626","article-title":"Epithelial expression and release of FGF-2 from heparan sulphate binding sites in bronchial tissue in asthma","volume":"59","author":"Shute","year":"2004","journal-title":"Thorax"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1165\/rcmb.4474","article-title":"Enhanced expression of fibroblast growth factorsand receptor FGFR-1 during vascular remodeling in chronic obstructive pulmonary disease","volume":"27","author":"Kranenburg","year":"2002","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.pharmthera.2007.07.003","article-title":"The nerve growth factor and its receptors in airway inflammatory diseases","volume":"117","author":"Frossard","year":"2008","journal-title":"Pharmacol. Ther."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/S0079-6123(03)46023-8","article-title":"Nerve growth factor and wound healing","volume":"146","author":"Kawamoto","year":"2004","journal-title":"Prog. Brain Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1016\/S0091-6749(97)70256-2","article-title":"Human CD4+ T cell clones produce and release nerve growth factor and express high-affinity nerve growth factor receptors","volume":"100","author":"Lambiase","year":"1997","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1159\/000053711","article-title":"Nerve growth factor induces airway hyperresponsiveness in mice","volume":"124","author":"Braun","year":"2001","journal-title":"Int. Arch. Allergy Immunol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1016\/j.jaci.2007.07.007","article-title":"Neuroimmune crosstalk in asthma: Dual role of the neurotrophin receptor p75NTR","volume":"120","author":"Nassenstein","year":"2007","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Wongtrakool, C., Grooms, K., Bijli, K.M., Crothers, K., Fitzpatrick, A.M., and Hart, C.M. (2014). Nicotine stimulates nerve growth factor in lung fibroblasts through an NFrB-dependent mechanism. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0109602"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1515\/hsz-2015-0208","article-title":"A role for NGF and its receptors TrKA and p75NTR in the progression of COPD","volume":"397","author":"Stabile","year":"2016","journal-title":"Biol. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Liu, P., Li, S., and Tang, L. (2021). Nerve Growth Factor: A Potential Therapeutic Target for Lung Diseases. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22179112"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1016\/j.chest.2021.04.020","article-title":"Stem Cell Therapy for COPD: Hope and Exploitation","volume":"160","author":"Glassberg","year":"2021","journal-title":"Chest"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2869","DOI":"10.2147\/COPD.S521659","article-title":"Biomarkers in COPD-Associated PH\/CCP: Circulating Molecules and Cell-Intrinsic Marker","volume":"20","author":"Wang","year":"2025","journal-title":"Int. J. Chronic Obstr. Pulm. Dis."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.rmed.2019.08.003","article-title":"VEGF and FGF-2: Promising targets for the treatment of respiratory disorders","volume":"156","author":"Laddha","year":"2019","journal-title":"Respir. Med."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Liu, S., Dong, J., Huang, W., and Yan, J. (2025). Immune imbalance underlying depressive symptoms in COPD patients: A study based on BDNF, PD-1, MMP-9, and inflammatory cytokines. Front. Med., 12.","DOI":"10.3389\/fmed.2025.1606630"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2037","DOI":"10.1016\/j.jaci.2018.04.010","article-title":"Blood eosinophil count thresholds and exacerbations in patients with chronic obstructive pulmonary disease","volume":"141","author":"Jeong","year":"2018","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1186\/s12931-023-02658-1","article-title":"Cell-free DNA levels associate with COPD exacerbations and mortality","volume":"25","author":"Ware","year":"2024","journal-title":"Respir. Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1186\/s12964-025-02042-0","article-title":"Mitochondrial DNA signals driving immune responses: Why, How, Where?","volume":"23","author":"Giordano","year":"2025","journal-title":"Cell Commun. Signal."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"163","DOI":"10.2147\/COPD.S42362","article-title":"Biomarkers in chronic obstructive pulmonary disease: Confusing or useful","volume":"9","author":"Stockley","year":"2014","journal-title":"Int. J. Chronic Obstr. Pulm. Dis."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Lu, Y.F., Goldstein, D.B., Angrist, M., and Cavalleri, G. (2014). Personalized medicine and human genetic diversity. Cold Spring Harb. Perspect. Med., 4.","DOI":"10.1101\/cshperspect.a008581"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/21\/10584\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,1]],"date-time":"2025-11-01T05:21:16Z","timestamp":1761974476000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/21\/10584"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,30]]},"references-count":68,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["ijms262110584"],"URL":"https:\/\/doi.org\/10.3390\/ijms262110584","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,30]]}}}