{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T23:49:07Z","timestamp":1790725747140,"version":"4.1.0"},"reference-count":55,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,8,23]],"date-time":"2021-08-23T00:00:00Z","timestamp":1629676800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,8,23]],"date-time":"2021-08-23T00:00:00Z","timestamp":1629676800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100003500","name":"University of Padova","doi-asserted-by":"crossref","award":["DOR funds"],"award-info":[{"award-number":["DOR funds"]}],"id":[{"id":"10.13039\/501100003500","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL139054"],"award-info":[{"award-number":["HL139054"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL091889"],"award-info":[{"award-number":["HL091889"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL132523"],"award-info":[{"award-number":["HL132523"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL130045"],"award-info":[{"award-number":["HL130045"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL098112"],"award-info":[{"award-number":["HL098112"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL056177"],"award-info":[{"award-number":["HL056177"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL149744"],"award-info":[{"award-number":["HL149744"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000066","name":"National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","award":["ES006614"],"award-info":[{"award-number":["ES006614"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI126614"],"award-info":[{"award-number":["AI126614"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000052","name":"NIH Office of the Director","doi-asserted-by":"publisher","award":["OD023282"],"award-info":[{"award-number":["OD023282"]}],"id":[{"id":"10.13039\/100000052","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007899","name":"University of Arizona","doi-asserted-by":"crossref","award":["TRIF grant"],"award-info":[{"award-number":["TRIF grant"]}],"id":[{"id":"10.13039\/100007899","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100007899","name":"University of Arizona","doi-asserted-by":"crossref","award":["RII COVID-19 seed grant (#002196)"],"award-info":[{"award-number":["RII COVID-19 seed grant (#002196)"]}],"id":[{"id":"10.13039\/100007899","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["DK103126"],"award-info":[{"award-number":["DK103126"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["GM136853"],"award-info":[{"award-number":["GM136853"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005640","name":"Flight Attendant Medical Research Institute","doi-asserted-by":"publisher","award":["YFAC141004"],"award-info":[{"award-number":["YFAC141004"]}],"id":[{"id":"10.13039\/100005640","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Pulm Med"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>How cigarette smoke (CS) and chronic obstructive pulmonary disease (COPD) affect severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection and severity is controversial. We investigated the effects of COPD and CS on the expression of SARS-CoV-2 entry receptor ACE2 in vivo in COPD patients and controls and in CS-exposed mice, and the effects of CS on SARS-CoV-2 infection in human bronchial epithelial cells in vitro.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>We quantified: (1) pulmonary ACE2 protein levels by immunostaining and ELISA, and both ACE2 and\/or TMPRSS2 mRNA levels by RT-qPCR in two independent human cohorts; and (2) pulmonary ACE2 protein levels by immunostaining and ELISA in C57BL\/6 WT mice exposed to air or CS for up to 6\u00a0months. The effects of CS exposure on SARS-CoV-2 infection were evaluated after in vitro infection of Calu-3 cells and differentiated human bronchial epithelial cells (HBECs), respectively.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>ACE2 protein and mRNA levels were decreased in peripheral airways from COPD patients versus controls but similar in central airways. Mice exposed to CS had decreased ACE2 protein levels in their bronchial and alveolar epithelia versus air-exposed mice. CS treatment decreased viral replication in Calu-3 cells, as determined by immunofluorescence staining for replicative double-stranded RNA (dsRNA) and western blot for viral N protein. Acute CS exposure decreased in vitro SARS-CoV-2 replication in HBECs, as determined by plaque assay and RT-qPCR.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>ACE2 levels were decreased in both bronchial and alveolar epithelial cells from COPD patients versus controls, and from CS-exposed versus air-exposed mice. CS-pre-exposure potently inhibited SARS-CoV-2 replication in vitro. These findings urge to investigate further the controversial effects of CS and COPD on SARS-CoV-2 infection.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12890-021-01639-8","type":"journal-article","created":{"date-parts":[[2021,8,23]],"date-time":"2021-08-23T14:05:14Z","timestamp":1629727514000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Paradoxical effects of cigarette smoke and COPD on SARS-CoV-2 infection and disease"],"prefix":"10.1186","volume":"21","author":[{"given":"M.","family":"Tomchaney","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Contoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Mayo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Baraldo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. R.","family":"Cabel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. A.","family":"Bull","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Lick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Malo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Knoper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. S.","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Tram","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Rojas-Quintero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Kraft","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. G.","family":"Ledford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y.","family":"Tesfaigzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F. D.","family":"Martinez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. A.","family":"Thorne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F.","family":"Kheradmand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. K.","family":"Campos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Papi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F.","family":"Polverino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,8,23]]},"reference":[{"key":"1639_CR1","doi-asserted-by":"publisher","first-page":"e57309","DOI":"10.7554\/eLife.57309","volume":"9","author":"YM Bar-On","year":"2020","unstructured":"Bar-On YM, Flamholz A, Phillips R, Milo R. SARS-CoV-2 (COVID-19) by the numbers. Elife. 2020;9:e57309. https:\/\/doi.org\/10.7554\/eLife.57309.","journal-title":"Elife"},{"key":"1639_CR2","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/S0140-6736(20)30183-5","volume":"395","author":"C Huang","year":"2020","unstructured":"Huang C, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497\u2013506. https:\/\/doi.org\/10.1016\/S0140-6736(20)30183-5.","journal-title":"Lancet"},{"key":"1639_CR3","doi-asserted-by":"publisher","first-page":"2620","DOI":"10.1172\/JCI137244","volume":"130","author":"G Chen","year":"2020","unstructured":"Chen G, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Investig. 2020;130:2620\u20139. https:\/\/doi.org\/10.1172\/JCI137244.","journal-title":"J Clin Investig"},{"key":"1639_CR4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.amjmed.2018.05.001","volume":"131","author":"F Polverino","year":"2018","unstructured":"Polverino F, Celli B. The challenge of controlling the COPD epidemic: unmet needs. Am J Med. 2018;131:1\u20136. https:\/\/doi.org\/10.1016\/j.amjmed.2018.05.001.","journal-title":"Am J Med"},{"key":"1639_CR5","doi-asserted-by":"publisher","first-page":"734","DOI":"10.1164\/rccm.201006-0833OC","volume":"183","author":"P Mallia","year":"2011","unstructured":"Mallia P, et al. Experimental rhinovirus infection as a human model of chronic obstructive pulmonary disease exacerbation. Am J Respir Crit Care Med. 2011;183:734\u201342. https:\/\/doi.org\/10.1164\/rccm.201006-0833OC.","journal-title":"Am J Respir Crit Care Med"},{"key":"1639_CR6","doi-asserted-by":"publisher","first-page":"627278","DOI":"10.3389\/fmed.2020.627278","volume":"7","author":"F Polverino","year":"2020","unstructured":"Polverino F, Kheradmand F. COVID-19, COPD, and AECOPD: immunological, epidemiological, and clinical aspects. Front Med (Lausanne). 2020;7:627278. https:\/\/doi.org\/10.3389\/fmed.2020.627278.","journal-title":"Front Med (Lausanne)"},{"key":"1639_CR7","doi-asserted-by":"publisher","first-page":"2001589","DOI":"10.1183\/13993003.01589-2020","volume":"56","author":"K Farsalinos","year":"2020","unstructured":"Farsalinos K, Angelopoulou A, Alexandris N, Poulas K. COVID-19 and the nicotinic cholinergic system. Eur Respir J. 2020;56:2001589. https:\/\/doi.org\/10.1183\/13993003.01589-2020.","journal-title":"Eur Respir J"},{"key":"1639_CR8","doi-asserted-by":"publisher","first-page":"1034","DOI":"10.1016\/S1473-3099(20)30371-6","volume":"20","author":"S de Lusignan","year":"2020","unstructured":"de Lusignan S, et al. Risk factors for SARS-CoV-2 among patients in the Oxford Royal College of General Practitioners Research and Surveillance Centre primary care network: a cross-sectional study. Lancet Infect Dis. 2020;20:1034\u201342. https:\/\/doi.org\/10.1016\/S1473-3099(20)30371-6.","journal-title":"Lancet Infect Dis"},{"key":"1639_CR9","doi-asserted-by":"publisher","first-page":"1054","DOI":"10.1016\/S0140-6736(20)30566-3","volume":"395","author":"F Zhou","year":"2020","unstructured":"Zhou F, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395:1054\u201362. https:\/\/doi.org\/10.1016\/S0140-6736(20)30566-3.","journal-title":"Lancet"},{"key":"1639_CR10","doi-asserted-by":"publisher","first-page":"1708","DOI":"10.1056\/NEJMoa2002032","volume":"382","author":"WJ Guan","year":"2020","unstructured":"Guan WJ, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382:1708\u201320. https:\/\/doi.org\/10.1056\/NEJMoa2002032.","journal-title":"N Engl J Med"},{"key":"1639_CR11","doi-asserted-by":"publisher","DOI":"10.1111\/all.14238","author":"JJ Zhang","year":"2020","unstructured":"Zhang JJ, et al. Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China. Allergy. 2020. https:\/\/doi.org\/10.1111\/all.14238.","journal-title":"Allergy"},{"key":"1639_CR12","doi-asserted-by":"publisher","first-page":"2052","DOI":"10.1001\/jama.2020.6775","volume":"323","author":"S Richardson","year":"2020","unstructured":"Richardson S, et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City Area. JAMA. 2020;323:2052\u20139. https:\/\/doi.org\/10.1001\/jama.2020.6775.","journal-title":"JAMA"},{"key":"1639_CR13","doi-asserted-by":"publisher","first-page":"2441","DOI":"10.1056\/NEJMoa2008975","volume":"382","author":"HR Reynolds","year":"2020","unstructured":"Reynolds HR, et al. Renin\u2013angiotensin\u2013aldosterone system inhibitors and risk of Covid-19. N Engl J Med. 2020;382:2441\u20138. https:\/\/doi.org\/10.1056\/NEJMoa2008975.","journal-title":"N Engl J Med"},{"key":"1639_CR14","doi-asserted-by":"publisher","first-page":"585866","DOI":"10.3389\/fcvm.2020.585866","volume":"7","author":"F Polverino","year":"2020","unstructured":"Polverino F, et al. Comorbidities, cardiovascular therapies, and COVID-19 mortality: a nationwide, Italian Observational Study (ItaliCO). Front Cardiovasc Med. 2020;7:585866. https:\/\/doi.org\/10.3389\/fcvm.2020.585866.","journal-title":"Front Cardiovasc Med"},{"key":"1639_CR15","doi-asserted-by":"publisher","first-page":"105941","DOI":"10.1016\/j.rmed.2020.105941","volume":"167","author":"G Lippi","year":"2020","unstructured":"Lippi G, Henry BM. Chronic obstructive pulmonary disease is associated with severe coronavirus disease 2019 (COVID-19). Respir Med. 2020;167:105941. https:\/\/doi.org\/10.1016\/j.rmed.2020.105941.","journal-title":"Respir Med"},{"key":"1639_CR16","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/j.cell.2020.02.052","volume":"181","author":"M Hoffmann","year":"2020","unstructured":"Hoffmann M, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181:271-280.e278. https:\/\/doi.org\/10.1016\/j.cell.2020.02.052.","journal-title":"Cell"},{"key":"1639_CR17","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1016\/j.cell.2020.05.042","volume":"182","author":"YJ Hou","year":"2020","unstructured":"Hou YJ, et al. SARS-CoV-2 reverse genetics reveals a variable infection gradient in the respiratory tract. Cell. 2020;182:429-446.e414. https:\/\/doi.org\/10.1016\/j.cell.2020.05.042.","journal-title":"Cell"},{"key":"1639_CR18","doi-asserted-by":"publisher","first-page":"1557","DOI":"10.1164\/rccm.202003-0693LE","volume":"201","author":"G Cai","year":"2020","unstructured":"Cai G, Bosse Y, Xiao F, Kheradmand F, Amos CI. Tobacco smoking increases the lung gene expression of ACE2, the receptor of SARS-CoV-2. Am J Respir Crit Care Med. 2020;201:1557\u20139. https:\/\/doi.org\/10.1164\/rccm.202003-0693LE.","journal-title":"Am J Respir Crit Care Med"},{"key":"1639_CR19","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1164\/rccm.202003-0541OC","volume":"202","author":"H Zhang","year":"2020","unstructured":"Zhang H, et al. Expression of the SARS-CoV-2 ACE2 receptor in the human airway epithelium. Am J Respir Crit Care Med. 2020;202:219\u201329. https:\/\/doi.org\/10.1164\/rccm.202003-0541OC.","journal-title":"Am J Respir Crit Care Med"},{"key":"1639_CR20","doi-asserted-by":"publisher","first-page":"2000688","DOI":"10.1183\/13993003.00688-2020","volume":"55","author":"JM Leung","year":"2020","unstructured":"Leung JM, et al. ACE-2 expression in the small airway epithelia of smokers and COPD patients: implications for COVID-19. Eur Respir J. 2020;55:2000688. https:\/\/doi.org\/10.1183\/13993003.00688-2020.","journal-title":"Eur Respir J"},{"key":"1639_CR21","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.02378-2020","author":"M Jacobs","year":"2020","unstructured":"Jacobs M, et al. Increased expression of ACE2, the SARS-CoV-2 entry receptor, in alveolar and bronchial epithelium of smokers and COPD subjects. Eur Respir J. 2020. https:\/\/doi.org\/10.1183\/13993003.02378-2020.","journal-title":"Eur Respir J"},{"key":"1639_CR22","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1007\/s12031-007-9025-7","volume":"35","author":"MF Ferrari","year":"2008","unstructured":"Ferrari MF, Raizada MK, Fior-Chadi DR. Differential regulation of the renin\u2013angiotensin system by nicotine in WKY and SHR glia. J Mol Neurosci. 2008;35:151\u201360. https:\/\/doi.org\/10.1007\/s12031-007-9025-7.","journal-title":"J Mol Neurosci"},{"key":"1639_CR23","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1007\/s12031-007-9006-x","volume":"33","author":"MF Ferrari","year":"2007","unstructured":"Ferrari MF, Raizada MK, Fior-Chadi DR. Nicotine modulates the renin-angiotensin system of cultured neurons and glial cells from cardiovascular brain areas of Wistar Kyoto and spontaneously hypertensive rats. J Mol Neurosci. 2007;33:284\u201393. https:\/\/doi.org\/10.1007\/s12031-007-9006-x.","journal-title":"J Mol Neurosci"},{"key":"1639_CR24","doi-asserted-by":"publisher","first-page":"R895","DOI":"10.1152\/ajpregu.00099.2018","volume":"315","author":"JM Oakes","year":"2018","unstructured":"Oakes JM, Fuchs RM, Gardner JD, Lazartigues E, Yue X. Nicotine and the renin\u2013angiotensin system. Am J Physiol Regul Integr Comp Physiol. 2018;315:R895\u2013906. https:\/\/doi.org\/10.1152\/ajpregu.00099.2018.","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"key":"1639_CR25","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1164\/rccm.202005-1646LE","volume":"202","author":"F Polverino","year":"2020","unstructured":"Polverino F. Cigarette smoking and COVID-19: a complex interaction. Am J Respir Crit Care Med. 2020;202:471\u20132. https:\/\/doi.org\/10.1164\/rccm.202005-1646LE.","journal-title":"Am J Respir Crit Care Med"},{"key":"1639_CR26","doi-asserted-by":"publisher","first-page":"796","DOI":"10.1164\/rccm.201010-1605OC","volume":"184","author":"PA Kirkham","year":"2011","unstructured":"Kirkham PA, et al. Oxidative stress-induced antibodies to carbonyl-modified protein correlate with severity of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2011;184:796\u2013802. https:\/\/doi.org\/10.1164\/rccm.201010-1605OC.","journal-title":"Am J Respir Crit Care Med"},{"key":"1639_CR27","doi-asserted-by":"publisher","first-page":"1434","DOI":"10.1164\/rccm.201903-0632LE","volume":"200","author":"JL Sullivan","year":"2019","unstructured":"Sullivan JL, et al. B cell adaptive immune profile in emphysema-predominant COPD. Am J Respir Crit Care Med. 2019;200:1434\u20139. https:\/\/doi.org\/10.1164\/rccm.201903-0632LE.","journal-title":"Am J Respir Crit Care Med"},{"key":"1639_CR28","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1038\/s41588-020-00759-x","volume":"53","author":"C Blume","year":"2021","unstructured":"Blume C, et al. A novel ACE2 isoform is expressed in human respiratory epithelia and is upregulated in response to interferons and RNA respiratory virus infection. Nat Genet. 2021;53:205\u201314. https:\/\/doi.org\/10.1038\/s41588-020-00759-x.","journal-title":"Nat Genet"},{"key":"1639_CR29","doi-asserted-by":"publisher","first-page":"1464","DOI":"10.1164\/rccm.201609-1765OC","volume":"195","author":"F Polverino","year":"2017","unstructured":"Polverino F, et al. A pilot study linking endothelial injury in lungs and kidneys in COPD. Am J Respir Crit Care Med. 2017;195:1464\u201376. https:\/\/doi.org\/10.1164\/rccm.201609-1765OC.","journal-title":"Am J Respir Crit Care Med"},{"key":"1639_CR30","doi-asserted-by":"publisher","first-page":"1254","DOI":"10.1164\/rccm.201707-1331OC","volume":"198","author":"F Polverino","year":"2018","unstructured":"Polverino F, et al. A disintegrin and metalloproteinase domain-8: a novel protective proteinase in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2018;198:1254\u201367. https:\/\/doi.org\/10.1164\/rccm.201707-1331OC.","journal-title":"Am J Respir Crit Care Med"},{"key":"1639_CR31","doi-asserted-by":"publisher","first-page":"1701009","DOI":"10.1183\/13993003.01009-2017","volume":"51","author":"GD Amatngalim","year":"2018","unstructured":"Amatngalim GD, et al. Aberrant epithelial differentiation by cigarette smoke dysregulates respiratory host defence. Eur Respir J. 2018;51:1701009. https:\/\/doi.org\/10.1183\/13993003.01009-2017.","journal-title":"Eur Respir J"},{"key":"1639_CR32","doi-asserted-by":"publisher","DOI":"10.1101\/2020.09.24.312553","author":"Y Li","year":"2020","unstructured":"Li Y, et al. SARS-CoV-2 induces double-stranded RNA-mediated innate immune responses in respiratory epithelial derived cells and cardiomyocytes. bioRxiv. 2020. https:\/\/doi.org\/10.1101\/2020.09.24.312553.","journal-title":"bioRxiv"},{"key":"1639_CR33","doi-asserted-by":"publisher","first-page":"588","DOI":"10.1038\/s41586-020-2575-3","volume":"585","author":"M Hoffmann","year":"2020","unstructured":"Hoffmann M, et al. Chloroquine does not inhibit infection of human lung cells with SARS-CoV-2. Nature. 2020;585:588\u201390. https:\/\/doi.org\/10.1038\/s41586-020-2575-3.","journal-title":"Nature"},{"key":"1639_CR34","doi-asserted-by":"publisher","first-page":"107863","DOI":"10.1016\/j.celrep.2020.107863","volume":"32","author":"ML Stanifer","year":"2020","unstructured":"Stanifer ML, et al. Critical role of type III interferon in controlling SARS-CoV-2 infection in human intestinal epithelial cells. Cell Rep. 2020;32:107863. https:\/\/doi.org\/10.1016\/j.celrep.2020.107863.","journal-title":"Cell Rep"},{"key":"1639_CR35","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1038\/s41586-020-2294-9","volume":"582","author":"T Thi Nhu Thao","year":"2020","unstructured":"Thi Nhu Thao T, et al. Rapid reconstruction of SARS-CoV-2 using a synthetic genomics platform. Nature. 2020;582:561\u20135. https:\/\/doi.org\/10.1038\/s41586-020-2294-9.","journal-title":"Nature"},{"key":"1639_CR36","doi-asserted-by":"publisher","first-page":"1488","DOI":"10.1016\/j.mayocp.2018.05.026","volume":"93","author":"S Mirza","year":"2018","unstructured":"Mirza S, Clay RD, Koslow MA, Scanlon PD. COPD guidelines: a review of the 2018 GOLD Report. Mayo Clin Proc. 2018;93:1488\u2013502. https:\/\/doi.org\/10.1016\/j.mayocp.2018.05.026.","journal-title":"Mayo Clin Proc"},{"key":"1639_CR37","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1164\/rccm.201505-0962OC","volume":"193","author":"F Polverino","year":"2016","unstructured":"Polverino F, et al. Evidence of renal and pulmonary endothelial dysfunction in chronic obstructive pulmonary disease (COPD). Am J Respir Crit Care Med. 2016;193:251\u20138.","journal-title":"Am J Respir Crit Care Med"},{"key":"1639_CR38","doi-asserted-by":"publisher","first-page":"1653","DOI":"10.1093\/ntr\/ntaa082","volume":"22","author":"R Patanavanich","year":"2020","unstructured":"Patanavanich R, Glantz SA. Smoking is associated with COVID-19 progression: a meta-analysis. Nicotine Tob Res. 2020;22:1653\u20136. https:\/\/doi.org\/10.1093\/ntr\/ntaa082.","journal-title":"Nicotine Tob Res"},{"key":"1639_CR39","doi-asserted-by":"publisher","first-page":"1045","DOI":"10.1002\/jmv.26389","volume":"93","author":"RK Reddy","year":"2021","unstructured":"Reddy RK, et al. The effect of smoking on COVID-19 severity: a systematic review and meta-analysis. J Med Virol. 2021;93:1045\u201356. https:\/\/doi.org\/10.1002\/jmv.26389.","journal-title":"J Med Virol"},{"key":"1639_CR40","doi-asserted-by":"publisher","first-page":"796","DOI":"10.3390\/biom11060796","volume":"11","author":"F Lunardi","year":"2021","unstructured":"Lunardi F, et al. Lower gene expression of angiotensin converting enzyme 2 receptor in lung tissues of smokers with COVID-19 pneumonia. Biomolecules. 2021;11:796. https:\/\/doi.org\/10.3390\/biom11060796.","journal-title":"Biomolecules"},{"key":"1639_CR41","doi-asserted-by":"publisher","first-page":"514","DOI":"10.1016\/j.devcel.2020.05.012","volume":"53","author":"JC Smith","year":"2020","unstructured":"Smith JC, et al. Cigarette smoke exposure and inflammatory signaling increase the expression of the SARS-CoV-2 receptor ACE2 in the respiratory tract. Dev Cell. 2020;53:514-529.e513. https:\/\/doi.org\/10.1016\/j.devcel.2020.05.012.","journal-title":"Dev Cell"},{"key":"1639_CR42","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1164\/rccm.202005-1651ED","volume":"202","author":"T Maes","year":"2020","unstructured":"Maes T, Bracke K, Brusselle GG. COVID-19, asthma, and inhaled corticosteroids: another beneficial effect of inhaled corticosteroids? Am J Respir Crit Care Med. 2020;202:8\u201310. https:\/\/doi.org\/10.1164\/rccm.202005-1651ED.","journal-title":"Am J Respir Crit Care Med"},{"key":"1639_CR43","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2020.09.034","author":"LJ Finney","year":"2020","unstructured":"Finney LJ, et al. Inhaled corticosteroids downregulate the SARS-CoV-2 receptor ACE2 in COPD through suppression of type I interferon. J Allergy Clin Immunol. 2020. https:\/\/doi.org\/10.1016\/j.jaci.2020.09.034.","journal-title":"J Allergy Clin Immunol"},{"key":"1639_CR44","doi-asserted-by":"publisher","first-page":"e9610","DOI":"10.15252\/msb.20209610","volume":"16","author":"F Hikmet","year":"2020","unstructured":"Hikmet F, et al. The protein expression profile of ACE2 in human tissues. Mol Syst Biol. 2020;16:e9610. https:\/\/doi.org\/10.15252\/msb.20209610.","journal-title":"Mol Syst Biol"},{"key":"1639_CR45","doi-asserted-by":"publisher","first-page":"756","DOI":"10.1164\/rccm.202001-0179LE","volume":"202","author":"Y Zhao","year":"2020","unstructured":"Zhao Y, et al. Single-cell RNA expression profiling of ACE2, the receptor of SARS-CoV-2. Am J Respir Crit Care Med. 2020;202:756\u20139. https:\/\/doi.org\/10.1164\/rccm.202001-0179LE.","journal-title":"Am J Respir Crit Care Med"},{"key":"1639_CR46","doi-asserted-by":"publisher","first-page":"546","DOI":"10.1038\/s41591-020-01227-z","volume":"27","author":"C Muus","year":"2021","unstructured":"Muus C, et al. Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics. Nat Med. 2021;27:546\u201359. https:\/\/doi.org\/10.1038\/s41591-020-01227-z.","journal-title":"Nat Med"},{"key":"1639_CR47","doi-asserted-by":"publisher","first-page":"L84","DOI":"10.1152\/ajplung.00071.2009","volume":"297","author":"HP Jia","year":"2009","unstructured":"Jia HP, et al. Ectodomain shedding of angiotensin converting enzyme 2 in human airway epithelia. Am J Physiol Lung Cell Mol Physiol. 2009;297:L84-96. https:\/\/doi.org\/10.1152\/ajplung.00071.2009.","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"1639_CR48","doi-asserted-by":"publisher","first-page":"30113","DOI":"10.1074\/jbc.M505111200","volume":"280","author":"DW Lambert","year":"2005","unstructured":"Lambert DW, et al. Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2). J Biol Chem. 2005;280:30113\u20139. https:\/\/doi.org\/10.1074\/jbc.M505111200.","journal-title":"J Biol Chem"},{"key":"1639_CR49","doi-asserted-by":"publisher","first-page":"14","DOI":"10.3109\/08958378.2013.850563","volume":"26","author":"T Xue","year":"2014","unstructured":"Xue T, Wei N, Xin Z, Qingyu X. Angiotensin-converting enzyme-2 overexpression attenuates inflammation in rat model of chronic obstructive pulmonary disease. Inhal Toxicol. 2014;26:14\u201322. https:\/\/doi.org\/10.3109\/08958378.2013.850563.","journal-title":"Inhal Toxicol"},{"key":"1639_CR50","doi-asserted-by":"publisher","first-page":"869","DOI":"10.1016\/j.stem.2020.11.010","volume":"27","author":"A Purkayastha","year":"2020","unstructured":"Purkayastha A, et al. Direct exposure to SARS-CoV-2 and cigarette smoke increases infection severity and alters the stem cell-derived airway repair response. Cell Stem Cell. 2020;27:869-875.e864. https:\/\/doi.org\/10.1016\/j.stem.2020.11.010.","journal-title":"Cell Stem Cell"},{"key":"1639_CR51","doi-asserted-by":"publisher","DOI":"10.1101\/2021.06.04.447156","author":"A Ghosh","year":"2021","unstructured":"Ghosh A, et al. Combustible and electronic cigarette exposures increase ACE2 activity and SARS-CoV-2 Spike binding. biorXiv. 2021. https:\/\/doi.org\/10.1101\/2021.06.04.447156.","journal-title":"biorXiv"},{"key":"1639_CR52","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1038\/nature03712","volume":"436","author":"Y Imai","year":"2005","unstructured":"Imai Y, et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature. 2005;436:112\u20136. https:\/\/doi.org\/10.1038\/nature03712.","journal-title":"Nature"},{"key":"1639_CR53","doi-asserted-by":"publisher","first-page":"681","DOI":"10.1038\/s41591-020-0868-6","volume":"26","author":"W Sungnak","year":"2020","unstructured":"Sungnak W, et al. SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nat Med. 2020;26:681\u20137. https:\/\/doi.org\/10.1038\/s41591-020-0868-6.","journal-title":"Nat Med"},{"key":"1639_CR54","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.25832","author":"M Hussain","year":"2020","unstructured":"Hussain M, et al. Structural variations in human ACE2 may influence its binding with SARS-CoV-2 spike protein. J Med Virol. 2020. https:\/\/doi.org\/10.1002\/jmv.25832.","journal-title":"J Med Virol"},{"key":"1639_CR55","doi-asserted-by":"publisher","first-page":"L232","DOI":"10.1152\/ajplung.00101.2015","volume":"310","author":"DC Lam","year":"2016","unstructured":"Lam DC, et al. Nicotinic acetylcholine receptor expression in human airway correlates with lung function. Am J Physiol Lung Cell Mol Physiol. 2016;310:L232-239. https:\/\/doi.org\/10.1152\/ajplung.00101.2015.","journal-title":"Am J Physiol Lung Cell Mol Physiol"}],"container-title":["BMC Pulmonary Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12890-021-01639-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12890-021-01639-8\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12890-021-01639-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,8,23]],"date-time":"2021-08-23T14:06:41Z","timestamp":1629727601000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcpulmmed.biomedcentral.com\/articles\/10.1186\/s12890-021-01639-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,23]]},"references-count":55,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["1639"],"URL":"https:\/\/doi.org\/10.1186\/s12890-021-01639-8","relation":{},"ISSN":["1471-2466"],"issn-type":[{"value":"1471-2466","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,23]]},"assertion":[{"value":"19 April 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 August 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 August 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The study conformed to the Declaration of Helsinki, and the work was approved by the institutional local ethic committees (University of Arizona IRB #1811124026 and University of Ferrara IRB #080399). Informed written consent was obtained from each subject. All the murine studies were approved by the Brigham and Women\u2019s Hospital (BWH) IACUC Committee, and performed in compliance with the BWH IACUC and ARRIVE guidelines.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All the authors consent for publication of this manuscript.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"M. Contoli has received personal fees from Chiesi, AstraZeneca, Boehringer-Ingelheim, Alk-Abello, GSK, Novartis, Zambon, and scientific grants from Chiesi and University of Ferrara, Italy. A. Papi: Board membership, consultancy, payment for lectures, grants for research, travel expenses reimbursement from GSK, AZ, Boehringer Ingelheim, Chiesi Farmaceutici, TEVA,\u2009Mundipharma, Zambon, Novartis, Menarini, Sanofi,Roche, Edmondpharma, Fondazione Maugeri, Fondazione Chiesi. None of the other authors have competing conflicts of interest to declare.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"275"}}