{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:08:19Z","timestamp":1792804099954,"version":"4.5.0"},"reference-count":47,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2020,10,27]],"date-time":"2020-10-27T00:00:00Z","timestamp":1603756800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81602028"],"award-info":[{"award-number":["81602028"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81702917"],"award-info":[{"award-number":["81702917"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81770045"],"award-info":[{"award-number":["81770045"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81802918"],"award-info":[{"award-number":["81802918"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004735","name":"Natural Science Foundation of\u00a0Hunan Province","doi-asserted-by":"publisher","award":["2019JJ50970"],"award-info":[{"award-number":["2019JJ50970"]}],"id":[{"id":"10.13039\/501100004735","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2021,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Angiotensin\u2010converting enzyme 2 (ACE2) has been identified as the functional receptor of severe acute respiratory syndrome coronavirus 2 (SARS\u2010CoV\u20102) and a target for disease prevention. However, the relationship between ACE2 expression and its clinical implications in SARS\u2010CoV\u20102 pathogenesis remains unknown. Here, we explored the location and expression of ACE2, and its correlation with gender, age, and cigarette smoke (CS), in a CS\u2010exposed mouse model and 224 non\u2010malignant lung tissues (125 non\u2010smokers, 81 current smokers, and 18 ex\u2010smokers) by immunohistochemistry. Moreover, the correlations of ACE2 with CS\u2010induced oxidative stress\u2010related markers, hypoxia\u2010inducible factor\u20101\u03b1 (HIF\u20101\u03b1), inducible nitric oxide synthase (iNOS), and 4\u2010hydroxynonenal (4\u2010HNE) were investigated. Chromatin immunoprecipitation and luciferase reporter assays identified the cause of ACE2 overexpression in human primary lung epithelial cells. We demonstrated that ACE2 was predominantly overexpressed on the apical surface of bronchial epithelium, while reduced in alveolar epithelium, owing to the dramatically decreased abundance of alveolar type II pneumocytes in CS\u2010exposed mouse lungs. Consistent with this, ACE2 was primarily significantly overexpressed in human bronchial and alveolar epithelial cells in smokers regardless of age or gender. Decreased ACE2 expression was observed in bronchial epithelial cells from ex\u2010smokers compared with current smokers, especially in those who had ceased smoking for more than 10\u2009years. Moreover, ACE2 expression was positively correlated with the levels of HIF\u20101\u03b1, iNOS, and 4\u2010HNE in both mouse and human bronchioles. The results were further validated using a publicly available dataset from The Cancer Genome Atlas (TCGA) and our previous integrated data from Affymetrix U133 Plus 2.0 microarray (AE\u2010meta). Finally, our results showed that HIF\u20101\u03b1 transcriptionally upregulates ACE2 expression. Our results indicate that smoking\u2010induced ACE2 overexpression in the apical surface of bronchial epithelial cells provides a route by which SARS\u2010CoV\u20102 enters host cells, which supports clinical relevance in attenuating the potential transmission risk of COVID\u201019 in smoking populations by smoking cessation. \u00a9 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/path.5555","type":"journal-article","created":{"date-parts":[[2020,9,29]],"date-time":"2020-09-29T17:42:44Z","timestamp":1601401364000},"page":"17-30","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":71,"title":["Overexpression of the\n                    <scp>SARS\u2010CoV<\/scp>\n                    \u20102 receptor\n                    <scp>ACE2<\/scp>\n                    is induced by cigarette smoke in bronchial and alveolar epithelia"],"prefix":"10.1002","volume":"253","author":[{"given":"Aibin","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Geriatrics, Respiratory Medicine Xiangya Hospital, Central South University  Changsha PR China"},{"name":"National Clinical Research Center for Geriatric Disorders Xiangya Hospital, Central South University  Changsha PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6036-2685","authenticated-orcid":false,"given":"Xin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Clinical Experimental Center, Jiangmen Key Laboratory of Clinical Biobanks and Translational Research Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat\u2010sen University  Jiangmen PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronggang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pathology, Jiangmen Central Hospital Affiliated Jiangmen Hospital of Sun Yat\u2010sen University  Jiangmen PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingzhu","family":"Zheng","sequence":"additional","affiliation":[{"name":"Clinical Experimental Center, Jiangmen Key Laboratory of Clinical Biobanks and Translational Research Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat\u2010sen University  Jiangmen PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shasha","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, Respiratory Medicine Xiangya Hospital, Central South University  Changsha PR China"},{"name":"National Clinical Research Center for Geriatric Disorders Xiangya Hospital, Central South University  Changsha PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Longxia","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, Respiratory Medicine Xiangya Hospital, Central South University  Changsha PR China"},{"name":"National Clinical Research Center for Geriatric Disorders Xiangya Hospital, Central South University  Changsha PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anhua","family":"Wu","sequence":"additional","affiliation":[{"name":"Center for Healthcare\u2010associated Infection Control Xiangya Hospital, Central South University  Changsha PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengping","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine Xiangya Hospital, Central South University  Changsha PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanming","family":"Huang","sequence":"additional","affiliation":[{"name":"Clinical Experimental Center, Jiangmen Key Laboratory of Clinical Biobanks and Translational Research Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat\u2010sen University  Jiangmen PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8500-5470","authenticated-orcid":false,"given":"Mingxuan","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, Respiratory Medicine Xiangya Hospital, Central South University  Changsha PR China"},{"name":"National Clinical Research Center for Geriatric Disorders Xiangya Hospital, Central South University  Changsha PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2534-8834","authenticated-orcid":false,"given":"Qiong","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, Respiratory Medicine Xiangya Hospital, Central South University  Changsha PR China"},{"name":"National Clinical Research Center for Geriatric Disorders Xiangya Hospital, Central South University  Changsha PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,10,27]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1038\/s41586-020-2012-7","article-title":"A pneumonia outbreak associated with a new coronavirus of probable bat origin","volume":"579","author":"Zhou P","year":"2020","journal-title":"Nature"},{"key":"e_1_2_7_3_1","unstructured":"World Health Organization. Weekly Operation Update on COVID\u201019 4 September 2020. [Accessed 6 September 2020]. Available from:https:\/\/www.who.int\/docs\/default-source\/coronaviruse\/situation-reports\/wou-4-september-2020-approved.pdf"},{"key":"e_1_2_7_4_1","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.ijid.2020.03.071","article-title":"Insight into 2019 novel coronavirus \u2013 an updated interim review and lessons from SARS\u2010CoV and MERS\u2010CoV","volume":"94","author":"Xie M","year":"2020","journal-title":"Int J Infect Dis"},{"key":"e_1_2_7_5_1","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.cell.2020.02.058","article-title":"Structure, function, and antigenicity of the SARS\u2010CoV\u20102 spike glycoprotein","volume":"181","author":"Walls AC","year":"2020","journal-title":"Cell"},{"key":"e_1_2_7_6_1","doi-asserted-by":"crossref","first-page":"33238","DOI":"10.1074\/jbc.M002615200","article-title":"A human homolog of angiotensin\u2010converting enzyme. 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Integrated analyses of single\u2010cell atlases reveal age gender and smoking status associations with cell type\u2010specific expression of mediators of SARS\u2010CoV\u20102 viral entry and s inflammatory programs in putative target cells.bioRxiv2020;https:\/\/doi.org\/10.1101\/2020.04.19.049254. 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Associations between COVID\u201019 infection tobacco smoking and nicotine use common respiratory conditions and inhaled corticosteroids: a prospective QResearch\u2010Case Mix Programme data linkage study January\u2013May 2020.medRxiv2020;https:\/\/doi.org\/10.1101\/2020.06.05.20116624. 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