{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T08:32:02Z","timestamp":1790757122294,"version":"4.1.0"},"reference-count":37,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2022,9,20]],"date-time":"2022-09-20T00:00:00Z","timestamp":1663632000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Reims Champagne-Ardenne (URCA)","award":["IRESP-19-PINACRAECOPD"],"award-info":[{"award-number":["IRESP-19-PINACRAECOPD"]}]},{"name":"French National Institute of Health and Medical Research (Inserm)","award":["IRESP-19-PINACRAECOPD"],"award-info":[{"award-number":["IRESP-19-PINACRAECOPD"]}]},{"name":"Research Institute in Public Health (IReSP) in association with the National Institute of Cancer (INCa)","award":["IRESP-19-PINACRAECOPD"],"award-info":[{"award-number":["IRESP-19-PINACRAECOPD"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Genome-wide association studies unveiled the associations between the single nucleotide polymorphism rs16969968 of CHRNA5, encoding the nicotinic acetylcholine receptor alpha5 subunit (\u03b15SNP), and nicotine addiction, cancer, and COPD independently. Here, we investigated \u03b15SNP-induced epithelial remodeling and inflammatory response in human COPD airways. We included 26 \u03b15SNP COPD patients and 18 wild-type \u03b15 COPD patients in a multi-modal study. A comparative histologic analysis was performed on formalin-fixed paraffin-embedded lung tissues. Isolated airway epithelial cells from bronchial brushings were cultivated in the air-liquid interface. Broncho-alveolar fluids were collected to detect inflammatory mediators. Ciliogenesis was altered in \u03b15SNP COPD bronchial and bronchiolar epithelia. Goblet cell hyperplasia was exacerbated in \u03b15SNP small airways. The broncho-alveolar fluids of \u03b15SNP COPD patients exhibited an increase in inflammatory mediators. The involvement of the rs16969968 polymorphism in airway epithelial remodeling and related inflammatory response in COPD prompts the development of innovative personalized diagnostic and therapeutic strategies.<\/jats:p>","DOI":"10.3390\/cells11192937","type":"journal-article","created":{"date-parts":[[2022,9,20]],"date-time":"2022-09-20T21:12:53Z","timestamp":1663708373000},"page":"2937","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["The Nicotinic Receptor Polymorphism rs16969968 Is Associated with Airway Remodeling and Inflammatory Dysregulation in COPD Patients"],"prefix":"10.3390","volume":"11","author":[{"given":"Lynda","family":"Saber Cherif","sequence":"first","affiliation":[{"name":"Inserm P3Cell UMR-S 1250, Universit\u00e9 de Reims Champagne-Ardenne, 51092 Reims, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zania","family":"Diabasana","sequence":"additional","affiliation":[{"name":"Inserm P3Cell UMR-S 1250, Universit\u00e9 de Reims Champagne-Ardenne, 51092 Reims, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanne-Marie","family":"Perotin","sequence":"additional","affiliation":[{"name":"Inserm P3Cell UMR-S 1250, Universit\u00e9 de Reims Champagne-Ardenne, 51092 Reims, France"},{"name":"D\u00e9partement des Maladies Respiratoires, CHU de Reims, 51092 Reims, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3128-9348","authenticated-orcid":false,"given":"Julien","family":"Ancel","sequence":"additional","affiliation":[{"name":"Inserm P3Cell UMR-S 1250, Universit\u00e9 de Reims Champagne-Ardenne, 51092 Reims, France"},{"name":"D\u00e9partement des Maladies Respiratoires, CHU de Reims, 51092 Reims, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laure M. G.","family":"Petit","sequence":"additional","affiliation":[{"name":"Inserm P3Cell UMR-S 1250, Universit\u00e9 de Reims Champagne-Ardenne, 51092 Reims, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ma\u00ebva A.","family":"Devilliers","sequence":"additional","affiliation":[{"name":"Inserm P3Cell UMR-S 1250, Universit\u00e9 de Reims Champagne-Ardenne, 51092 Reims, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnaud","family":"Bonnomet","sequence":"additional","affiliation":[{"name":"Inserm P3Cell UMR-S 1250, Universit\u00e9 de Reims Champagne-Ardenne, 51092 Reims, France"},{"name":"Plateforme d\u2019Imagerie Cellulaire et Tissulaire (PICT), Universit\u00e9 de Reims Champagne-Ardenne, 51097 Reims, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Lalun","sequence":"additional","affiliation":[{"name":"Inserm P3Cell UMR-S 1250, Universit\u00e9 de Reims Champagne-Ardenne, 51092 Reims, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gonzague","family":"Delepine","sequence":"additional","affiliation":[{"name":"Inserm P3Cell UMR-S 1250, Universit\u00e9 de Reims Champagne-Ardenne, 51092 Reims, France"},{"name":"D\u00e9partement de Chirurgie Thoracique, CHU de Reims, 51092 Reims, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uwe","family":"Maskos","sequence":"additional","affiliation":[{"name":"CNRS UMR 3571, Unit\u00e9 de Neurobiologie Int\u00e9grative des Syst\u00e8mes Cholinergiques, Institut Pasteur de Paris, Universit\u00e9 de Paris Cit\u00e9, 75006 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4043-6429","authenticated-orcid":false,"given":"Philippe","family":"Gosset","sequence":"additional","affiliation":[{"name":"CNRS UMR 9017, Inserm U1019, Institut Pasteur de Lille, Universit\u00e9 de Lille, CHU de Lille, 59000 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myriam","family":"Polette","sequence":"additional","affiliation":[{"name":"Inserm P3Cell UMR-S 1250, Universit\u00e9 de Reims Champagne-Ardenne, 51092 Reims, France"},{"name":"D\u00e9partement de Biopathologie, CHU de Reims, 51092 Reims, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana\u00eblle","family":"Muggeo","sequence":"additional","affiliation":[{"name":"Inserm P3Cell UMR-S 1250, Universit\u00e9 de Reims Champagne-Ardenne, 51092 Reims, France"},{"name":"Laboratoire de Bact\u00e9riologie, Virologie, Hygi\u00e8ne Hospitali\u00e8re, Parasitologie, Mycologie, CHU de Reims, 51092 Reims, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3795-0398","authenticated-orcid":false,"given":"Thomas","family":"Guillard","sequence":"additional","affiliation":[{"name":"Inserm P3Cell UMR-S 1250, Universit\u00e9 de Reims Champagne-Ardenne, 51092 Reims, France"},{"name":"Laboratoire de Bact\u00e9riologie, Virologie, Hygi\u00e8ne Hospitali\u00e8re, Parasitologie, Mycologie, CHU de Reims, 51092 Reims, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ga\u00ebtan","family":"Desl\u00e9e","sequence":"additional","affiliation":[{"name":"Inserm P3Cell UMR-S 1250, Universit\u00e9 de Reims Champagne-Ardenne, 51092 Reims, France"},{"name":"D\u00e9partement des Maladies Respiratoires, CHU de Reims, 51092 Reims, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1725-371X","authenticated-orcid":false,"given":"Val\u00e9rian","family":"Dormoy","sequence":"additional","affiliation":[{"name":"Inserm P3Cell UMR-S 1250, Universit\u00e9 de Reims Champagne-Ardenne, 51092 Reims, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1111\/resp.12660","article-title":"Global burden of COPD","volume":"21","author":"Tan","year":"2016","journal-title":"Respirology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2227","DOI":"10.1016\/S0140-6736(22)00470-6","article-title":"Chronic obstructive pulmonary disease","volume":"399","author":"Christenson","year":"2022","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1055\/s-0035-1549450","article-title":"Gene\u2013Environment Interaction from International Cohorts: Impact on Development and Evolution of Occupational and Environmental Lung and Airway Disease","volume":"36","author":"Gaffney","year":"2015","journal-title":"Semin. Respir. Crit. Care Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1900651","DOI":"10.1183\/13993003.00651-2019","article-title":"Airway inflammation in COPD: Progress to precision medicine","volume":"54","author":"Brightling","year":"2019","journal-title":"Eur. Respir. J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1164\/rccm.202009-3442OC","article-title":"Necroptosis Signaling Promotes Inflammation, Airway Remodeling, and Emphysema in Chronic Obstructive Pulmonary Disease","volume":"204","author":"Lu","year":"2021","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Vitenberga, Z., Pilmane, M., and Babjoni\u0161eva, A. (2019). An Insight into COPD Morphopathogenesis: Chronic Inflammation, Remodeling, and Antimicrobial Defense. Medicina, 55.","DOI":"10.3390\/medicina55080496"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3341","DOI":"10.2147\/COPD.S176122","article-title":"Role of inflammatory cells in airway remodeling in COPD","volume":"13","author":"Wang","year":"2018","journal-title":"Int. J. Chronic Obstr. Pulm. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"L232","DOI":"10.1152\/ajplung.00101.2015","article-title":"Nicotinic acetylcholine receptor expression in human airway correlates with lung function","volume":"310","author":"Lam","year":"2016","journal-title":"Am. J. Physiol.-Lung Cell. Mol. Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/s41588-018-0321-7","article-title":"New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries","volume":"51","author":"Shrine","year":"2019","journal-title":"Nat. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1164\/rccm.201202-0366OC","article-title":"Genome-Wide Association Studies Identify CHRNA5\/3 and HTR4 in the Development of Airflow Obstruction","volume":"186","author":"Wilk","year":"2012","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/j.ccm.2020.05.003","article-title":"Alpha-1 Antitrypsin Deficiency Associated COPD","volume":"41","author":"Strange","year":"2020","journal-title":"Clin. Chest Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1056\/NEJMra1910234","article-title":"Alpha1-Antitrypsin Deficiency","volume":"382","author":"Strnad","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1176\/appi.ajp.2008.07111711","article-title":"Variants in Nicotinic Receptors and Risk for Nicotine Dependence","volume":"165","author":"Bierut","year":"2008","journal-title":"Am. J. Psychiatry"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1111\/jnc.14989","article-title":"The nicotinic receptor alpha5 coding polymorphism rs16969968 as a major target in disease: Functional dissection and remaining challenges","volume":"154","author":"Maskos","year":"2020","journal-title":"J. Neurochem."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Weiss, R.B., Baker, T.B., Cannon, D.S., von Niederhausern, A., Dunn, D.M., Matsunami, N., Singh, N.A., Baird, L., Coon, H., and McMahon, W.M. (2008). A Candidate Gene Approach Identifies the CHRNA5-A3-B4 Region as a Risk Factor for Age-Dependent Nicotine Addiction. PLoS Genet., 4.","DOI":"10.1371\/journal.pgen.1000125"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1038\/ng.109","article-title":"Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1","volume":"40","author":"Amos","year":"2008","journal-title":"Nat. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1038\/nature06885","article-title":"A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25","volume":"452","author":"Hung","year":"2008","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1038\/nature06846","article-title":"A variant associated with nicotine dependence, lung cancer and peripheral arterial disease","volume":"452","author":"Thorgeirsson","year":"2008","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"The Tobacco and Genetics Consortium (2010). Genome-wide meta-analyses identify multiple loci associated with smoking behavior. Nat. Genet., 42, 441\u2013447.","DOI":"10.1038\/ng.571"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1136\/thoraxjnl-2020-214839","article-title":"Chr15q25 genetic variant (rs16969968) independently confers risk of lung cancer, COPD and smoking intensity in a prospective study of high-risk smokers","volume":"76","author":"Hopkins","year":"2021","journal-title":"Thorax"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Pillai, S.G., Ge, D., Zhu, G., Kong, X., Shianna, K.V., Need, A., Feng, S., Hersh, C.P., Bakke, P., and Gulsvick, A. (2009). A Genome-Wide Association Study in Chronic Obstructive Pulmonary Disease (COPD): Identification of Two Major Susceptibility Loci. PLoS Genet., 5.","DOI":"10.1371\/journal.pgen.1000421"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Diabasana, Z., Perotin, J.-M., Belgacemi, R., Ancel, J., Mulette, P., Launois, C., Delepine, G., Dubernard, X., M\u00e9rol, J.-C., and Ruaux, C. (2021). Chr15q25 Genetic Variant rs16969968 Alters Cell Differentiation in Respiratory Epithelia. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22136657"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"6384","DOI":"10.1038\/s41467-021-26637-6","article-title":"An innate contribution of human nicotinic receptor polymorphisms to COPD-like lesions","volume":"12","author":"Routhier","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1186\/s12931-020-01478-x","article-title":"Sonic hedgehog signalling as a potential endobronchial biomarker in COPD","volume":"21","author":"Ancel","year":"2020","journal-title":"Respir. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"16878","DOI":"10.1038\/s41598-017-17204-5","article-title":"QuPath: Open source software for digital pathology image analysis","volume":"7","author":"Bankhead","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1016\/j.jcf.2020.12.023","article-title":"Extended-culture and culture-independent molecular analysis of the airway microbiota in cystic fibrosis following CFTR modulation with ivacaftor","volume":"20","author":"Einarsson","year":"2021","journal-title":"J. Cyst. Fibros."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1016\/j.jcf.2019.02.012","article-title":"Assessment of stability and fluctuations of cultured lower airway bacterial communities in people with cystic fibrosis","volume":"18","author":"Sherrard","year":"2019","journal-title":"J. Cyst. Fibros."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1056\/NEJMoa1106955","article-title":"Small-Airway Obstruction and Emphysema in Chronic Obstructive Pulmonary Disease","volume":"365","author":"McDonough","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"781797","DOI":"10.3389\/fmicb.2021.781797","article-title":"Extended Bacteria Culture-Based Clustering Identifies a Phenotype Associating Increased Cough and Enterobacterales in Stable Chronic Obstructive Pulmonary Disease","volume":"12","author":"Muggeo","year":"2021","journal-title":"Front. Microbiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"a028191","DOI":"10.1101\/cshperspect.a028191","article-title":"Ciliopathies","volume":"9","author":"Braun","year":"2017","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1800122","DOI":"10.1183\/13993003.00122-2018","article-title":"Alteration of primary cilia in COPD","volume":"52","author":"Perotin","year":"2018","journal-title":"Eur. Respir. J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1186\/s12931-021-01665-4","article-title":"CiliOPD: A ciliopathy-associated COPD endotype","volume":"22","author":"Perotin","year":"2021","journal-title":"Respir. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.chest.2017.11.008","article-title":"Mucins, Mucus, and Goblet Cells","volume":"154","author":"Ma","year":"2018","journal-title":"Chest"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1016\/S2213-2600(21)00079-5","article-title":"Airway mucin MUC5AC and MUC5B concentrations and the initiation and progression of chronic obstructive pulmonary disease: An analysis of the SPIROMICS cohort","volume":"9","author":"Radicioni","year":"2021","journal-title":"Lancet Respir. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1164\/rccm.202006-2248OC","article-title":"Mucus Plugs and Emphysema in the Pathophysiology of Airflow Obstruction and Hypoxemia in Smokers","volume":"203","author":"Dunican","year":"2021","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1093\/intimm\/14.2.147","article-title":"Human T cell leukemia virus type-I Tax activates human macrophage inflammatory protein-3\u03b1\/CCL20 gene transcription via the NF-\u03baB pathway","volume":"14","author":"Imaizumi","year":"2002","journal-title":"Int. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Burgoyne, R.A., Fisher, A.J., and Borthwick, L.A. (2021). The Role of Epithelial Damage in the Pulmonary Immune Response. Cells, 10.","DOI":"10.3390\/cells10102763"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/19\/2937\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:35:48Z","timestamp":1760142948000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/19\/2937"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,20]]},"references-count":37,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["cells11192937"],"URL":"https:\/\/doi.org\/10.3390\/cells11192937","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,20]]}}}