{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T12:03:52Z","timestamp":1792065832406,"version":"4.4.0"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2014,6,1]],"date-time":"2014-06-01T00:00:00Z","timestamp":1401580800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The airway epithelium constitutes an essential immunological and cytoprotective barrier to inhaled insults, such as cigarette smoke, environmental particles, or viruses. Although bronchial epithelial integrity is crucial for airway homeostasis, defective epithelial barrier function contributes to chronic obstructive pulmonary disease (COPD). Tight junctions at the apical side of epithelial cell\u2013cell contacts determine epithelial permeability. Cigarette smoke exposure, the major risk factor for COPD, is suggested to impair tight junction integrity; however, detailed mechanisms thereof remain elusive. We investigated whether cigarette smoke extract (CSE) and transforming growth factor (TGF)-\u03b21 affected tight junction integrity. Exposure of human bronchial epithelial cells (16HBE14o\u2212) and differentiated primary human bronchial epithelial cells (pHBECs) to CSE significantly disrupted tight junction integrity and barrier function. Specifically, CSE decreased transepithelial electrical resistance (TEER) and tight junction\u2013associated protein levels. Zonula occludens (ZO)-1 and ZO-2 protein levels were significantly reduced and dislocated from the cell membrane, as observed by fractionation and immunofluorescence analysis. These findings were reproduced in isolated bronchi exposed to CSE ex vivo, as detected by real-time quantitative reverse-transcriptase PCR and immunohistochemistry. Combined treatment of 16HBE14o\u2212 cells or pHBECs with CSE and TGF-\u03b21 restored ZO-1 and ZO-2 levels. TGF-\u03b21 cotreatment restored membrane localization of ZO-1 and ZO-2 protein and prevented CSE-mediated TEER decrease. In conclusion, CSE led to the disruption of tight junctions of human bronchial epithelial cells, and TGF-\u03b21 counteracted this CSE-induced effect. Thus, TGF-\u03b21 may serve as a protective factor for bronchial epithelial cell homeostasis in diseases such as COPD.<\/jats:p>","DOI":"10.1165\/rcmb.2013-0090oc","type":"journal-article","created":{"date-parts":[[2014,6,1]],"date-time":"2014-06-01T16:16:46Z","timestamp":1401639406000},"page":"1040-1052","source":"Crossref","is-referenced-by-count":104,"title":["Cigarette Smoke\u2013Induced Disruption of Bronchial Epithelial Tight Junctions Is Prevented by Transforming Growth Factor-\u03b2"],"prefix":"10.1093","volume":"50","author":[{"given":"Andrea C.","family":"Schamberger","sequence":"first","affiliation":[{"name":"Comprehensive Pneumology Center, Institute of Lung Biology and Disease, University Hospital, Ludwig-Maximilians-University and Helmholtz Zentrum M\u00fcnchen, Member of the German Center for Lung Research, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikica","family":"Mise","sequence":"additional","affiliation":[{"name":"Comprehensive Pneumology Center, Institute of Lung Biology and Disease, University Hospital, Ludwig-Maximilians-University and Helmholtz Zentrum M\u00fcnchen, Member of the German Center for Lung Research, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Jia","sequence":"additional","affiliation":[{"name":"Comprehensive Pneumology Center, Institute of Lung Biology and Disease, University Hospital, Ludwig-Maximilians-University and Helmholtz Zentrum M\u00fcnchen, Member of the German Center for Lung Research, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuelle","family":"Genoyer","sequence":"additional","affiliation":[{"name":"Comprehensive Pneumology Center, Institute of Lung Biology and Disease, University Hospital, Ludwig-Maximilians-University and Helmholtz Zentrum M\u00fcnchen, Member of the German Center for Lung Research, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali \u00d6.","family":"Yildirim","sequence":"additional","affiliation":[{"name":"Comprehensive Pneumology Center, Institute of Lung Biology and Disease, University Hospital, Ludwig-Maximilians-University and Helmholtz Zentrum M\u00fcnchen, Member of the German Center for Lung Research, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silke","family":"Meiners","sequence":"additional","affiliation":[{"name":"Comprehensive Pneumology Center, Institute of Lung Biology and Disease, University Hospital, Ludwig-Maximilians-University and Helmholtz Zentrum M\u00fcnchen, Member of the German Center for Lung Research, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Eickelberg","sequence":"additional","affiliation":[{"name":"Comprehensive Pneumology Center, Institute of Lung Biology and Disease, University Hospital, Ludwig-Maximilians-University and Helmholtz Zentrum M\u00fcnchen, Member of the German Center for Lung Research, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2014,6,1]]},"reference":[{"key":"2026030623181542500_bib1","author":"WHO"},{"key":"2026030623181542500_bib2","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1016\/S0140-6736(11)60968-9","article-title":"Chronic obstructive pulmonary disease","volume":"379","author":"Decramer","year":"2012","journal-title":"Lancet"},{"key":"2026030623181542500_bib3","author":"Global Initiative for Chronic Obstructive Lung Disease"},{"key":"2026030623181542500_bib4","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1136\/thx.51.5.465","article-title":"Mechanisms of cigarette smoke induced increased airspace permeability","volume":"51","author":"Li","year":"1996","journal-title":"Thorax"},{"key":"2026030623181542500_bib5","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1165\/ajrcmb.23.4.3959","article-title":"Effect of cigarette smoke on the permeability and IL-1beta and sICAM-1 release from cultured human bronchial epithelial cells of never-smokers, smokers, and patients with chronic obstructive pulmonary disease","volume":"23","author":"Rusznak","year":"2000","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026030623181542500_bib6","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/S0140-6736(80)90493-6","article-title":"Increased alveolar epithelial permeability in cigarette smokers","volume":"1","author":"Jones","year":"1980","journal-title":"Lancet"},{"key":"2026030623181542500_bib7","doi-asserted-by":"crossref","first-page":"2109","DOI":"10.1152\/jappl.1989.66.5.2109","article-title":"Respiratory epithelial permeability after cigarette smoke exposure in guinea pigs","volume":"66","author":"Burns","year":"1989","journal-title":"J Appl Physiol (1985)"},{"key":"2026030623181542500_bib8","first-page":"75","article-title":"Penetration of the respiratory epithelium of guinea pigs following exposure to cigarette smoke","volume":"31","author":"Simani","year":"1974","journal-title":"Lab Invest"},{"key":"2026030623181542500_bib9","first-page":"320","article-title":"Airway permeability to horseradish peroxidase in guinea pigs: the repair phase after injury by cigarette smoke","volume":"123","author":"Hulbert","year":"1981","journal-title":"Am Rev Respir Dis"},{"key":"2026030623181542500_bib10","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/j.bbamem.2007.09.032","article-title":"The cytoplasmic plaque of tight junctions: a scaffolding and signalling center","volume":"1778","author":"Guillemot","year":"2008","journal-title":"Biochim Biophys Acta"},{"key":"2026030623181542500_bib11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0079-6107(02)00037-8","article-title":"Tight junction proteins","volume":"81","author":"Gonz\u00e1lez-Mariscal","year":"2003","journal-title":"Prog Biophys Mol Biol"},{"key":"2026030623181542500_bib12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0003-2670(03)00078-3","article-title":"Electron spin resonance and spin trap investigation of free radicals in cigarette smoke: development of a quantification procedure","volume":"481","author":"Baum","year":"2003","journal-title":"Anal Chim Acta"},{"key":"2026030623181542500_bib13","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1183\/09031936.00193810","article-title":"Cigarette smoke impairs airway epithelial barrier function and cell-cell contact recovery","volume":"39","author":"Heijink","year":"2012","journal-title":"Eur Respir J"},{"key":"2026030623181542500_bib14","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1080\/08958370600985768","article-title":"Cellular mechanisms of mainstream cigarette smoke-induced lung epithelial tight junction permeability changes in vitro","volume":"19","author":"Olivera","year":"2007","journal-title":"Inhal Toxicol"},{"key":"2026030623181542500_bib15","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1007\/s00018-010-0500-x","article-title":"Cigarette smoking reprograms apical junctional complex molecular architecture in the human airway epithelium in vivo","volume":"68","author":"Shaykhiev","year":"2011","journal-title":"Cell Mol Life Sci"},{"key":"2026030623181542500_bib16","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1016\/j.tiv.2010.11.011","article-title":"Chronic exposure to cigarette smoke condensate in vitro induces epithelial to mesenchymal transition-like changes in human bronchial epithelial cells, BEAS-2B","volume":"25","author":"Veljkovic","year":"2011","journal-title":"Toxicol In Vitro"},{"key":"2026030623181542500_bib17","doi-asserted-by":"crossref","first-page":"2501","DOI":"10.1183\/09031936.96.09122501","article-title":"Diverse cellular TGF-beta 1 and TGF-beta 3 gene expression in normal human and murine lung","volume":"9","author":"Coker","year":"1996","journal-title":"Eur Respir J"},{"key":"2026030623181542500_bib18","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1146\/annurev.pathol.4.110807.092145","article-title":"The pathology of chronic obstructive pulmonary disease","volume":"4","author":"Hogg","year":"2009","journal-title":"Annu Rev Pathol"},{"key":"2026030623181542500_bib19","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1164\/ajrccm.158.6.9803053","article-title":"Transforming growth factor beta1 and recruitment of macrophages and mast cells in airways in chronic obstructive pulmonary disease","volume":"158","author":"de Boer","year":"1998","journal-title":"Am J Respir Crit Care Med"},{"key":"2026030623181542500_bib20","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1136\/thorax.2003.005769","article-title":"Transforming growth factor-beta1 genotype and susceptibility to chronic obstructive pulmonary disease","volume":"59","author":"Wu","year":"2004","journal-title":"Thorax"},{"key":"2026030623181542500_bib21","doi-asserted-by":"crossref","first-page":"5730","DOI":"10.4049\/jimmunol.153.12.5730","article-title":"Regulation of intestinal epithelial barrier function by TGF-beta 1: evidence for its role in abrogating the effect of a T cell cytokine","volume":"153","author":"Planchon","year":"1994","journal-title":"J Immunol"},{"key":"2026030623181542500_bib22","doi-asserted-by":"crossref","first-page":"5635","DOI":"10.1128\/IAI.68.10.5635-5644.2000","article-title":"Transforming growth factor beta1 ameliorates intestinal epithelial barrier disruption by Cryptosporidium parvum in vitro in the absence of mucosal T lymphocytes","volume":"68","author":"Roche","year":"2000","journal-title":"Infect Immun"},{"key":"2026030623181542500_bib23","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1002\/(SICI)1097-4652(199910)181:1<55::AID-JCP6>3.0.CO;2-M","article-title":"Transforming growth factor-beta1 preserves epithelial barrier function: identification of receptors, biochemical intermediates, and cytokine antagonists","volume":"181","author":"Planchon","year":"1999","journal-title":"J Cell Physiol"},{"key":"2026030623181542500_bib24","doi-asserted-by":"crossref","first-page":"2382","DOI":"10.4049\/jimmunol.159.5.2382","article-title":"Superantigen activation of immune cells evokes epithelial (T84) transport and barrier abnormalities via IFN-gamma and TNF alpha: inhibition of increased permeability, but not diminished secretory responses by TGF-beta2","volume":"159","author":"McKay","year":"1997","journal-title":"J Immunol"},{"key":"2026030623181542500_bib25","doi-asserted-by":"crossref","first-page":"1587","DOI":"10.1016\/S0002-9440(10)61243-6","article-title":"Transforming growth factor-beta regulation of epithelial tight junction proteins enhances barrier function and blocks enterohemorrhagic Escherichia coli O157:H7-induced increased permeability","volume":"167","author":"Howe","year":"2005","journal-title":"Am J Pathol"},{"key":"2026030623181542500_bib26","doi-asserted-by":"crossref","first-page":"L814","DOI":"10.1152\/ajplung.00128.2012","article-title":"Acute cigarette smoke exposure impairs proteasome function in the lung","volume":"303","author":"van Rijt","year":"2012","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2026030623181542500_bib27","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1183\/09031936.00155107","article-title":"Keratinocyte growth factor protects against Clara cell injury induced by naphthalene","volume":"32","author":"Yildirim","year":"2008","journal-title":"Eur Respir J"},{"key":"2026030623181542500_bib28","doi-asserted-by":"crossref","first-page":"31393","DOI":"10.1074\/jbc.M112.357624","article-title":"Zyxin is a transforming growth factor-\u03b2 (TGF-\u03b2)\/Smad3 target gene that regulates lung cancer cell motility via integrin \u03b15\u03b21","volume":"287","author":"Mise","year":"2012","journal-title":"J Biol Chem"},{"key":"2026030623181542500_bib29","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1164\/rccm.200910-1560OC","article-title":"Activation of the WNT\/\u03b2-catenin pathway attenuates experimental emphysema","volume":"183","author":"Kneidinger","year":"2011","journal-title":"Am J Respir Crit Care Med"},{"key":"2026030623181542500_bib30","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1111\/j.1398-9995.2008.01861.x","article-title":"Cigarette smoke facilitates allergen penetration across respiratory epithelium","volume":"64","author":"Gangl","year":"2009","journal-title":"Allergy"},{"key":"2026030623181542500_bib31","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1016\/j.cell.2006.06.043","article-title":"ZO-1 and ZO-2 independently determine where claudins are polymerized in tight-junction strand formation","volume":"126","author":"Umeda","year":"2006","journal-title":"Cell"},{"key":"2026030623181542500_bib32","doi-asserted-by":"crossref","first-page":"1502","DOI":"10.1378\/chest.08-1780","article-title":"Bronchial airway epithelial cell damage following exposure to cigarette smoke includes disassembly of tight junction components mediated by the extracellular signal-regulated kinase 1\/2 pathway","volume":"135","author":"Petecchia","year":"2009","journal-title":"Chest"},{"key":"2026030623181542500_bib33","doi-asserted-by":"crossref","first-page":"44785","DOI":"10.1074\/jbc.M406563200","article-title":"Establishment and characterization of cultured epithelial cells lacking expression of ZO-1","volume":"279","author":"Umeda","year":"2004","journal-title":"J Biol Chem"},{"key":"2026030623181542500_bib34","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1128\/MCB.06029-11","article-title":"Occludin: one protein, many forms","volume":"32","author":"Cummins","year":"2012","journal-title":"Mol Cell Biol"},{"key":"2026030623181542500_bib35","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1183\/09031936.00208511","article-title":"What shall we do with the damaged proteins in lung disease? Ask the proteasome!","volume":"40","author":"Meiners","year":"2012","journal-title":"Eur Respir J"},{"key":"2026030623181542500_bib36","first-page":"497","article-title":"Obtaining of measles virus haemagglutinin from strain L-16 grown in primary cell cultures","volume":"19","author":"Dorofeyeva","year":"1975","journal-title":"Acta Virol"},{"key":"2026030623181542500_bib37","doi-asserted-by":"crossref","first-page":"3206","DOI":"10.1016\/j.febslet.2008.08.013","article-title":"Cigarette smoking products suppress anti-viral effects of type i interferon via phosphorylation-dependent downregulation of its receptor","volume":"582","author":"HuangFu","year":"2008","journal-title":"FEBS Lett"},{"key":"2026030623181542500_bib38","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1096\/fj.06-7729com","article-title":"Epidermal growth factor receptor exposed to cigarette smoke is aberrantly activated and undergoes perinuclear trafficking","volume":"22","author":"Khan","year":"2008","journal-title":"FASEB J"},{"key":"2026030623181542500_bib39","doi-asserted-by":"crossref","first-page":"10201","DOI":"10.1074\/jbc.M111384200","article-title":"The tight junction-specific protein occludin is a functional target of the E3 ubiquitin-protein ligase itch","volume":"277","author":"Traweger","year":"2002","journal-title":"J Biol Chem"},{"key":"2026030623181542500_bib40","doi-asserted-by":"crossref","first-page":"G50","DOI":"10.1152\/ajpgi.00494.2010","article-title":"ERK is involved in EGF-mediated protection of tight junctions, but not adherens junctions, in acetaldehyde-treated Caco-2 cell monolayers","volume":"301","author":"Samak","year":"2011","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"2026030623181542500_bib41","doi-asserted-by":"crossref","first-page":"L56","DOI":"10.1152\/ajplung.00159.2010","article-title":"The Rac1\/JNK pathway is critical for EGFR-dependent barrier formation in human airway epithelial cells","volume":"300","author":"Terakado","year":"2011","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2026030623181542500_bib42","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/j.jaci.2011.05.038","article-title":"Defective epithelial barrier function in asthma","volume":"128","author":"Xiao","year":"2011","journal-title":"J Allergy Clin Immunol"},{"key":"2026030623181542500_bib43","doi-asserted-by":"crossref","first-page":"1476","DOI":"10.1164\/ajrccm.163.6.9908135","article-title":"Increased expression of transforming growth factor-beta1 in small airway epithelium from tobacco smokers and patients with chronic obstructive pulmonary disease (COPD)","volume":"163","author":"Takizawa","year":"2001","journal-title":"Am J Respir Crit Care Med"},{"key":"2026030623181542500_bib44","doi-asserted-by":"crossref","first-page":"2667","DOI":"10.1038\/ncomms3667","article-title":"Differential regulation of the REG\u03b3-proteasome pathway by p53\/TGF-\u03b2 signalling and mutant p53 in cancer cells","volume":"4","author":"Ali","year":"2013","journal-title":"Nat Commun"},{"key":"2026030623181542500_bib45","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1080\/13550280801993630","article-title":"Human immunodeficiency virus type 1 gp120-mediated disruption of tight junction proteins by induction of proteasome-mediated degradation of zonula occludens-1 and -2 in human brain microvascular endothelial cells","volume":"14","author":"Nakamuta","year":"2008","journal-title":"J Neurovirol"},{"key":"2026030623181542500_bib46","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1183\/09031936.00065809","article-title":"Characterisation of cell adhesion in airway epithelial cell types using electric cell-substrate impedance sensing","volume":"35","author":"Heijink","year":"2010","journal-title":"Eur Respir J"},{"key":"2026030623181542500_bib47","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1038\/sj.emboj.7600605","article-title":"E-cadherin is essential for in vivo epidermal barrier function by regulating tight junctions","volume":"24","author":"Tunggal","year":"2005","journal-title":"EMBO J"}],"container-title":["American Journal of Respiratory Cell and Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article-pdf\/50\/6\/1040\/67118124\/ajrcmb_50_6_1040.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article-pdf\/50\/6\/1040\/67118124\/ajrcmb_50_6_1040.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,7]],"date-time":"2026-03-07T04:18:37Z","timestamp":1772857117000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article\/50\/6\/1040\/8491881"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,6,1]]},"references-count":47,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2014,6,1]]},"published-print":{"date-parts":[[2014,6,1]]}},"URL":"https:\/\/doi.org\/10.1165\/rcmb.2013-0090oc","relation":{},"ISSN":["1044-1549","1535-4989"],"issn-type":[{"value":"1044-1549","type":"print"},{"value":"1535-4989","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2014,6]]},"published":{"date-parts":[[2014,6,1]]}}}