{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T15:59:56Z","timestamp":1792166396204,"version":"4.4.0"},"reference-count":104,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2022,11,3]],"date-time":"2022-11-03T00:00:00Z","timestamp":1667433600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Netherlands Food and Consumer Product Safety Authority (NVWA)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Chronic obstructive pulmonary disease (COPD) is a devastating lung disease primarily caused by exposure to cigarette smoke (CS). During the pyrolysis and combustion of tobacco, reactive aldehydes such as acetaldehyde, acrolein, and formaldehyde are formed, which are known to be involved in respiratory toxicity. Although CS-induced mitochondrial dysfunction has been implicated in the pathophysiology of COPD, the role of aldehydes therein is incompletely understood. To investigate this, we used a physiologically relevant in vitro exposure model of differentiated human primary bronchial epithelial cells (PBEC) exposed to CS (one cigarette) or a mixture of acetaldehyde, acrolein, and formaldehyde (at relevant concentrations of one cigarette) or air, in a continuous flow system using a puff-like exposure protocol. Exposure of PBEC to CS resulted in elevated IL-8 cytokine and mRNA levels, increased abundance of constituents associated with autophagy, decreased protein levels of molecules associated with the mitophagy machinery, and alterations in the abundance of regulators of mitochondrial biogenesis. Furthermore, decreased transcript levels of basal epithelial cell marker KRT5 were reported after CS exposure. Only parts of these changes were replicated in PBEC upon exposure to a combination of acetaldehyde, acrolein, and formaldehyde. More specifically, aldehydes decreased MAP1LC3A mRNA (autophagy) and BNIP3 protein (mitophagy) and increased ESRRA protein (mitochondrial biogenesis). These data suggest that other compounds in addition to aldehydes in CS contribute to CS-induced dysregulation of constituents controlling mitochondrial content and function in airway epithelial cells.<\/jats:p>","DOI":"10.3390\/cells11213481","type":"journal-article","created":{"date-parts":[[2022,11,4]],"date-time":"2022-11-04T03:28:10Z","timestamp":1667532490000},"page":"3481","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Smoking-Associated Exposure of Human Primary Bronchial Epithelial Cells to Aldehydes: Impact on Molecular Mechanisms Controlling Mitochondrial Content and Function"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2537-3036","authenticated-orcid":false,"given":"Christy B. M.","family":"Tulen","sequence":"first","affiliation":[{"name":"School of Nutrition and Translational Research in Metabolism (NUTRIM), Department of Pharmacology and Toxicology, Maastricht University Medical Center+, 6200 MD Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evert","family":"Duistermaat","sequence":"additional","affiliation":[{"name":"National Institute for Public Health and the Environment (RIVM), 3721 MA Bilthoven, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes W. J. M.","family":"Cremers","sequence":"additional","affiliation":[{"name":"National Institute for Public Health and the Environment (RIVM), 3721 MA Bilthoven, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walther N. M.","family":"Klerx","sequence":"additional","affiliation":[{"name":"National Institute for Public Health and the Environment (RIVM), 3721 MA Bilthoven, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul H. B.","family":"Fokkens","sequence":"additional","affiliation":[{"name":"National Institute for Public Health and the Environment (RIVM), 3721 MA Bilthoven, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na\u00f6mi","family":"Weibolt","sequence":"additional","affiliation":[{"name":"National Institute for Public Health and the Environment (RIVM), 3721 MA Bilthoven, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nico","family":"Kloosterboer","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Maastricht University Medical Center+, 6229 HX Maastricht, The Netherlands"},{"name":"Primary Lung Culture (PLUC) Facility, Maastricht University Medical Center+, 6200 MD Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mieke A.","family":"Dentener","sequence":"additional","affiliation":[{"name":"Primary Lung Culture (PLUC) Facility, Maastricht University Medical Center+, 6200 MD Maastricht, The Netherlands"},{"name":"School of Nutrition and Translational Research in Metabolism (NUTRIM), Department of Respiratory Medicine, Maastricht University Medical Center+, 6200 MD Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric R.","family":"Gremmer","sequence":"additional","affiliation":[{"name":"National Institute for Public Health and the Environment (RIVM), 3721 MA Bilthoven, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phyllis J. J.","family":"Jessen","sequence":"additional","affiliation":[{"name":"School of Nutrition and Translational Research in Metabolism (NUTRIM), Department of Pharmacology and Toxicology, Maastricht University Medical Center+, 6200 MD Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evi J. C.","family":"Koene","sequence":"additional","affiliation":[{"name":"School of Nutrition and Translational Research in Metabolism (NUTRIM), Department of Pharmacology and Toxicology, Maastricht University Medical Center+, 6200 MD Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lou","family":"Maas","sequence":"additional","affiliation":[{"name":"School of Nutrition and Translational Research in Metabolism (NUTRIM), Department of Pharmacology and Toxicology, Maastricht University Medical Center+, 6200 MD Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antoon","family":"Opperhuizen","sequence":"additional","affiliation":[{"name":"School of Nutrition and Translational Research in Metabolism (NUTRIM), Department of Pharmacology and Toxicology, Maastricht University Medical Center+, 6200 MD Maastricht, The Netherlands"},{"name":"Office of Risk Assessment and Research, Netherlands Food and Consumer Product Safety Authority (NVWA), 3511 GG Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederik-Jan","family":"van Schooten","sequence":"additional","affiliation":[{"name":"School of Nutrition and Translational Research in Metabolism (NUTRIM), Department of Pharmacology and Toxicology, Maastricht University Medical Center+, 6200 MD Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7187-0121","authenticated-orcid":false,"given":"Yvonne C. M.","family":"Staal","sequence":"additional","affiliation":[{"name":"National Institute for Public Health and the Environment (RIVM), 3721 MA Bilthoven, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander H. V.","family":"Remels","sequence":"additional","affiliation":[{"name":"School of Nutrition and Translational Research in Metabolism (NUTRIM), Department of Pharmacology and Toxicology, Maastricht University Medical Center+, 6200 MD Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,3]]},"reference":[{"key":"ref_1","unstructured":"GBD 2015 Tobacco Collaborators (2017). Smoking prevalence and attributable disease burden in 195 countries and territories, 1990\u20132015: A systematic analysis from the Global Burden of Disease Study 2015. Lancet, 389, 1885\u20131906."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1056\/NEJMra1900500","article-title":"Update on Clinical Aspects of Chronic Obstructive Pulmonary Disease","volume":"381","author":"Celli","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_3","unstructured":"Rodgman, A., and Perfetti, T.A. (2013). The Chemical Components of Tobacco and Tobacco Smoke, CRC Press."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1136\/tc.2007.024158","article-title":"Mandated lowering of toxicants in cigarette smoke: A description of the World Health Organization TobReg proposal","volume":"17","author":"Burns","year":"2008","journal-title":"Tob. Control"},{"key":"ref_5","unstructured":"Cheah, N.P. (2016). Volatile Aldehydes in Tobacco Smoke: Source Fate and Risk. [Ph.D. Thesis, Maastricht University]."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1093\/toxsci\/kfv071","article-title":"Comparative Risks of Aldehyde Constituents in Cigarette Smoke Using Transient Computational Fluid Dynamics\/Physiologically Based Pharmacokinetic Models of the Rat and Human Respiratory Tracts","volume":"146","author":"Corley","year":"2015","journal-title":"Toxicol. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1080\/08958378.2021.1909678","article-title":"Risk assessment of components in tobacco smoke and e-cigarette aerosols: A pragmatic choice of dose metrics","volume":"33","author":"Bos","year":"2021","journal-title":"Inhal. Toxicol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1093\/toxsci\/kfw051","article-title":"Proposed Mode of Action for Acrolein Respiratory Toxicity Associated with Inhaled Tobacco Smoke","volume":"151","author":"Yeager","year":"2016","journal-title":"Toxicol. Sci."},{"key":"ref_9","first-page":"1","article-title":"Formaldehyde toxicity reports from in vitro and in vivo studies: A review and updated data","volume":"45","author":"Bernardini","year":"2020","journal-title":"Drug Chem. Toxicol."},{"key":"ref_10","unstructured":"National Research Council (US) Committee (2009). Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants, National Academies Press (US)."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1021\/acs.chemrestox.7b00342","article-title":"Cigarette Filter Ventilation and Smoking Protocol Influence Aldehyde Smoke Yields","volume":"31","author":"Pauwels","year":"2018","journal-title":"Chem. Res. Toxicol."},{"key":"ref_12","unstructured":"World Health Organization Framework Convention on Tobacco Control Secretariat (2012). Partial Guidelines for Implementation of Articles 9 and 10\u2014Regulation of the Contents of Tobacco Products and Regulation of Tobacco Product Disclosures, World Health Organization."},{"key":"ref_13","unstructured":"World Health Organization, and World Health Organization Tobacco Free Initiative (2008). The Scientific Basis of Tobacco Product Regulation: Second Report of a WHO Study Group, World Health Organization."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.tiv.2017.11.005","article-title":"Human lung epithelial cell cultures for analysis of inhaled toxicants: Lessons learned and future directions","volume":"47","author":"Hiemstra","year":"2018","journal-title":"Toxicol. Vitro"},{"key":"ref_15","first-page":"332","article-title":"Cell number and cell characteristics of the normal human lung","volume":"126","author":"Crapo","year":"1982","journal-title":"Am. Rev. Respir. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.1183\/09031936.00141514","article-title":"The innate immune function of airway epithelial cells in inflammatory lung disease","volume":"45","author":"Hiemstra","year":"2015","journal-title":"Eur. Respir. J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1172\/JCI81113","article-title":"Mitochondria in lung disease","volume":"126","author":"Cloonan","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"L149","DOI":"10.1152\/ajplung.00329.2019","article-title":"Mitochondria: At the crossroads of regulating lung epithelial cell function in chronic obstructive pulmonary disease","volume":"318","author":"Aghapour","year":"2020","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/j.ccm.2007.06.008","article-title":"Pathogenesis of Chronic Obstructive Pulmonary Disease","volume":"28","author":"MacNee","year":"2007","journal-title":"Clin. Chest Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"15047","DOI":"10.1038\/s41598-019-51517-x","article-title":"Mitochondrial dysfunction increases pro-inflammatory cytokine production and impairs repair and corticosteroid responsiveness in lung epithelium","volume":"9","author":"Hoffmann","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Patergnani, S., Bouhamida, E., Leo, S., Pinton, P., and Rimessi, A. (2021). Mitochondrial Oxidative Stress and \u201cMito-Inflammation\u201d: Actors in the Diseases. Biomedicines, 9.","DOI":"10.3390\/biomedicines9020216"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2510","DOI":"10.1016\/j.jmb.2019.10.015","article-title":"Ubiquitin and Receptor-Dependent Mitophagy Pathways and Their Implication in Neurodegeneration","volume":"432","author":"Fritsch","year":"2020","journal-title":"J. Mol. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/j.cmet.2005.05.004","article-title":"Metabolic control through the PGC-1 family of transcription coactivators","volume":"1","author":"Lin","year":"2005","journal-title":"Cell Metab."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1016\/j.bbamcr.2010.09.019","article-title":"Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network","volume":"1813","author":"Scarpulla","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1038\/nrm3877","article-title":"Mitochondrial dynamics and inheritance during cell division, development and disease","volume":"15","author":"Mishra","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Hara, H., Kuwano, K., and Araya, J. (2018). Mitochondrial Quality Control in COPD and IPF. Cells, 7.","DOI":"10.3390\/cells7080086"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"S266","DOI":"10.1513\/AnnalsATS.201808-585MG","article-title":"Mitochondrial Dysfunction as a Pathogenic Mediator of Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis","volume":"15","author":"Ryter","year":"2018","journal-title":"Ann. Am. Thorac. Soc."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1165\/rcmb.2013-0523OC","article-title":"Short-term cigarette smoke exposure leads to metabolic alterations in lung alveolar cells","volume":"51","author":"Agarwal","year":"2014","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1038\/nm.4021","article-title":"Mitochondrial iron chelation ameliorates cigarette smoke-induced bronchitis and emphysema in mice","volume":"22","author":"Cloonan","year":"2016","journal-title":"Nat. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"L737","DOI":"10.1152\/ajplung.00146.2013","article-title":"Mitochondrial fragmentation in cigarette smoke-induced bronchial epithelial cell senescence","volume":"305","author":"Hara","year":"2013","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1186\/1465-9921-14-97","article-title":"Prolonged cigarette smoke exposure alters mitochondrial structure and function in airway epithelial cells","volume":"14","author":"Hoffmann","year":"2013","journal-title":"Respir. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.fct.2018.02.013","article-title":"Assessment of mitochondrial function following short- and long-term exposure of human bronchial epithelial cells to total particulate matter from a candidate modified-risk tobacco product and reference cigarettes","volume":"115","author":"Malinska","year":"2018","journal-title":"Food Chem. Toxicol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3987","DOI":"10.1172\/JCI74985","article-title":"Mitophagy-dependent necroptosis contributes to the pathogenesis of COPD","volume":"124","author":"Mizumura","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.toxlet.2019.09.022","article-title":"Mitochondrial dysfunction is associated with Miro1 reduction in lung epithelial cells by cigarette smoke","volume":"317","author":"Sundar","year":"2019","journal-title":"Toxicol. Lett."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.redox.2018.03.006","article-title":"N-acetyl cysteine reverts the proinflammatory state induced by cigarette smoke extract in lung Calu-3 cells","volume":"16","author":"Valdivieso","year":"2018","journal-title":"Redox Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"L109","DOI":"10.1152\/ajplung.90461.2008","article-title":"Lipid-soluble components in cigarette smoke induce mitochondrial production of reactive oxygen species in lung epithelial cells","volume":"297","author":"Rezayat","year":"2009","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1016\/j.bbrc.2020.02.160","article-title":"Cigarette smoke extract increases mitochondrial membrane permeability through activation of adenine nucleotide translocator (ANT) in lung epithelial cells","volume":"525","author":"Wu","year":"2020","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2912","DOI":"10.1096\/fj.14-268276","article-title":"Impaired mitophagy leads to cigarette smoke stress-induced cellular senescence: Implications for chronic obstructive pulmonary disease","volume":"29","author":"Ahmad","year":"2015","journal-title":"FASEB J."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Chen, Z.H., Kim, H.P., Sciurba, F.C., Lee, S.J., Feghali-Bostwick, C., Stolz, D.B., Dhir, R., Landreneau, R.J., Schuchert, M.J., and Yousem, S.A. (2008). Egr-1 regulates autophagy in cigarette smoke-induced chronic obstructive pulmonary disease. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0003316"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1080\/15548627.2015.1017190","article-title":"PARK2-mediated mitophagy is involved in regulation of HBEC senescence in COPD pathogenesis","volume":"11","author":"Ito","year":"2015","journal-title":"Autophagy"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"138","DOI":"10.4046\/trd.2017.0115","article-title":"The Phosphodiesterase 4 Inhibitor Roflumilast Protects against Cigarette Smoke Extract-Induced Mitophagy-Dependent Cell Death in Epithelial Cells","volume":"81","author":"Kyung","year":"2018","journal-title":"Tuberc. Respir. Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1880","DOI":"10.1096\/fj.201700571R","article-title":"Sphingolipid regulation of lung epithelial cell mitophagy and necroptosis during cigarette smoke exposure","volume":"32","author":"Mizumura","year":"2018","journal-title":"FASEB J."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.toxlet.2018.12.007","article-title":"Whole cigarette smoke condensates induce ferroptosis in human bronchial epithelial cells","volume":"303","author":"Park","year":"2019","journal-title":"Toxicol. Lett."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.tiv.2018.01.011","article-title":"Quercetogetin protects against cigarette smoke extract-induced apoptosis in epithelial cells by inhibiting mitophagy","volume":"48","author":"Son","year":"2018","journal-title":"Toxicol. Vitro"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Song, C., Luo, B., and Gong, L. (2017). Resveratrol reduces the apoptosis induced by cigarette smoke extract by upregulating MFN2. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0175009"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"14210","DOI":"10.1002\/jcp.28117","article-title":"Nix\/BNIP3L-dependent mitophagy accounts for airway epithelial cell injury induced by cigarette smoke","volume":"234","author":"Zhang","year":"2019","journal-title":"J. Cell Physiol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Wang, S., Song, X., Wei, L., Liu, Q., Li, C., and Wang, J. (Curr. Mol. Med., 2022). Role of mitophagy in cigarette smoke-induced lung epithelial cell injury in vitro, Curr. Mol. Med., ahead of print.","DOI":"10.2174\/1566524023666221025100002"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.toxlet.2015.05.007","article-title":"Association between the aldehyde dehydrogenase 2*2 allele and smoking-related chronic airway obstruction in a Japanese general population: A pilot study","volume":"236","author":"Morita","year":"2015","journal-title":"Toxicol. Lett."},{"key":"ref_49","first-page":"286","article-title":"Altered lung function and structure in the rat after subchronic exposure to acrolein","volume":"133","author":"Costa","year":"1986","journal-title":"Am. Rev. Respir. Dis."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"dmm049247","DOI":"10.1242\/dmm.049247","article-title":"Dysregulated mitochondrial metabolism upon cigarette smoke exposure in various human bronchial epithelial cell models","volume":"15","author":"Tulen","year":"2022","journal-title":"Dis. Models Mech."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1186\/s12931-022-02150-2","article-title":"Early transcriptional responses of bronchial epithelial cells to whole cigarette smoke mirror those of in-vivo exposed human bronchial mucosa","volume":"23","author":"Mahbub","year":"2022","journal-title":"Respir. Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"L51","DOI":"10.1152\/ajplung.2000.278.1.L51","article-title":"Regulation of SLPI and elafin release from bronchial epithelial cells by neutrophil defensins","volume":"278","author":"Kuijpers","year":"2000","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1016\/j.molimm.2006.04.008","article-title":"Epithelial differentiation is a determinant in the production of eotaxin-2 and -3 by bronchial epithelial cells in response to IL-4 and IL-13","volume":"44","author":"Zuyderduyn","year":"2007","journal-title":"Mol. Immunol."},{"key":"ref_54","unstructured":"World Health Organization, and TobLabNet (2012). SOP 1\u2014Standard Operating Procedure for Intense Smoking of Cigarettes, World Health Organization."},{"key":"ref_55","unstructured":"World Health Organization, and TobLabNet (2018). SOP 8\u2014Standard Operating Procedure for Determination of Aldehydes in Mainstream Cigarette Smoke under ISO and Intense Smoking Conditions, World Health Organization."},{"key":"ref_56","unstructured":"Rasband, W.S. (2019). ImageJ, 1997\u20132018, National Institutes of Health."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/B978-0-12-391857-4.00009-4","article-title":"Methods for cell and particle tracking","volume":"504","author":"Meijering","year":"2012","journal-title":"Methods Enzymol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1770","DOI":"10.1164\/ajrccm.155.5.9154890","article-title":"Cigarette smoke induces interleukin-8 release from human bronchial epithelial cells","volume":"155","author":"Mio","year":"1997","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"L839","DOI":"10.1152\/ajplung.90570.2008","article-title":"alpha, beta-Unsaturated aldehydes contained in cigarette smoke elicit IL-8 release in pulmonary cells through mitogen-activated protein kinases","volume":"296","author":"Moretto","year":"2009","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.tiv.2017.09.016","article-title":"Inflammatory effects of acrolein, crotonaldehyde and hexanal vapors on human primary bronchial epithelial cells cultured at air-liquid interface","volume":"46","author":"Dwivedi","year":"2018","journal-title":"Toxicol. Vitro"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1165\/rcmb.2013-0348TR","article-title":"Molecular processes that drive cigarette smoke-induced epithelial cell fate of the lung","volume":"50","author":"Nyunoya","year":"2014","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1016\/j.redox.2014.01.004","article-title":"A novel method for pulmonary research: Assessment of bioenergetic function at the air-liquid interface","volume":"2","author":"Xu","year":"2014","journal-title":"Redox Biol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"L1158","DOI":"10.1152\/ajplung.00414.2019","article-title":"Real-time measurement of cellular bioenergetics in fully differentiated human nasal epithelial cells grown at air-liquid-interface","volume":"318","author":"Mavin","year":"2020","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"S40","DOI":"10.1513\/AnnalsATS.201507-450MG","article-title":"Autophagy: Friend or Foe in Lung Disease?","volume":"13","author":"Mizumura","year":"2016","journal-title":"Ann. Am. Thorac. Soc."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.pupt.2019.04.002","article-title":"Dual role of autophagy\/mitophagy in chronic obstructive pulmonary disease","volume":"56","author":"Jiang","year":"2019","journal-title":"Pulm. Pharmacol. Ther."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"5425","DOI":"10.4049\/jimmunol.1001603","article-title":"Identification of an autophagy defect in smokers\u2019 alveolar macrophages","volume":"185","author":"Monick","year":"2010","journal-title":"J. Immunol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"630","DOI":"10.4161\/onci.20297","article-title":"Insufficient autophagy promotes bronchial epithelial cell senescence in chronic obstructive pulmonary disease","volume":"1","author":"Fujii","year":"2012","journal-title":"Oncoimmunology"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1042\/CS20210900","article-title":"Autophagy in asthma and chronic obstructive pulmonary disease","volume":"136","author":"Barnes","year":"2022","journal-title":"Clin. Sci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1016\/j.bbamcr.2014.11.002","article-title":"Quantitative analysis of mitochondrial morphology and membrane potential in living cells using high-content imaging, machine learning, and morphological binning","volume":"1853","author":"Leonard","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"70406","DOI":"10.18632\/oncotarget.19710","article-title":"Acrolein induces mtDNA damages, mitochondrial fission and mitophagy in human lung cells","volume":"8","author":"Wang","year":"2017","journal-title":"Oncotarget"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"153129","DOI":"10.1016\/j.tox.2022.153129","article-title":"Acrolein inhalation acutely affects the regulation of mitochondrial metabolism in rat lung","volume":"469","author":"Tulen","year":"2022","journal-title":"Toxicology"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"748233718796347","DOI":"10.1177\/0748233718796347","article-title":"Formaldehyde inhalation triggers autophagy in rat lung tissues","volume":"34","author":"Liu","year":"2018","journal-title":"Toxicol. Ind. Health"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Giordano, L., Gregory, A.D., Verdaguer, M.P., Ware, S.A., Harvey, H., DeVallance, E., Brzoska, T., Sundd, P., Zhang, Y., and Sciurba, F.C. (2022). Extracellular release of mitochondrial DNA: Triggered by cigaretee smoke and detected in COPD. Cells, 11.","DOI":"10.3390\/cells11030369"},{"key":"ref_74","first-page":"5478","article-title":"A new antioxidant formulation reduces the apoptotic and damaging effect of cigarette smoke extract on human bronchial epithelial cells","volume":"21","author":"Vanella","year":"2017","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1007\/s10522-013-9454-3","article-title":"A cigarette component acrolein induces accelerated senescence in human diploid fibroblast IMR-90 cells","volume":"14","author":"Luo","year":"2013","journal-title":"Biogerontology"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"L840","DOI":"10.1152\/ajplung.00155.2013","article-title":"Cigarette smoke-induced mitochondrial fragmentation and dysfunction in human airway smooth muscle","volume":"306","author":"Aravamudan","year":"2014","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"L895","DOI":"10.1152\/ajplung.00180.2014","article-title":"Cigarette smoke extract affects mitochondrial function in alveolar epithelial cells","volume":"307","author":"Ballweg","year":"2014","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1007\/s10565-008-9115-5","article-title":"Acetaldehyde-induced mitochondrial dysfunction sensitizes hepatocytes to oxidative damage","volume":"25","author":"Bucio","year":"2009","journal-title":"Cell Biol. Toxicol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"L764","DOI":"10.1152\/ajplung.00165.2013","article-title":"Metabolic shift in lung alveolar cell mitochondria following acrolein exposure","volume":"305","author":"Agarwal","year":"2013","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.mito.2006.04.003","article-title":"Acrolein is a mitochondrial toxin: Effects on respiratory function and enzyme activities in isolated rat liver mitochondria","volume":"6","author":"Sun","year":"2006","journal-title":"Mitochondrion"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/0003-9861(69)90344-0","article-title":"Inhibition by formaldehyde of energy transfer and related processes in rat liver mitochondria. II. Effects on energy-linked reactions in intact mitochondria and phosphorylating particles","volume":"132","author":"Frisell","year":"1969","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1007\/s10565-015-9309-6","article-title":"Effects of formaldehyde on mitochondrial dysfunction and apoptosis in SK-N-SH neuroblastoma cells","volume":"31","author":"Zerin","year":"2015","journal-title":"Cell Biol. Toxicol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"8163","DOI":"10.1038\/srep08163","article-title":"Cigarette smoke alters primary human bronchial epithelial cell differentiation at the air-liquid interface","volume":"5","author":"Schamberger","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_84","first-page":"e52325","article-title":"Impact assessment of repeated exposure of organotypic 3D bronchial and nasal tissue culture models to whole cigarette smoke","volume":"96","author":"Kuehn","year":"2015","journal-title":"J. Vis. Exp."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/j.etp.2015.04.006","article-title":"Ciliatoxicity in human primary bronchiolar epithelial cells after repeated exposure at the air\u2013liquid interface with native mainstream smoke of K3R4F cigarettes with and without charcoal filter","volume":"67","author":"Aufderheide","year":"2015","journal-title":"Exp. Toxicol. Pathol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1186\/s12931-019-1226-4","article-title":"Effects of cigarette smoke on barrier function and tight junction proteins in the bronchial epithelium: Protective role of cathelicidin LL-37","volume":"20","author":"Tatsuta","year":"2019","journal-title":"Respir. Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1435","DOI":"10.3892\/ijmm.2015.2133","article-title":"Caveolin-1 aggravates cigarette smoke extract-induced MUC5AC secretion in human airway epithelial cells","volume":"35","author":"Yu","year":"2015","journal-title":"Int. J. Mol. Med."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1165\/rcmb.2013-0363OC","article-title":"FOXJ1 prevents cilia growth inhibition by cigarette smoke in human airway epithelium in vitro","volume":"51","author":"Brekman","year":"2014","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"6257","DOI":"10.1038\/s41598-020-63345-5","article-title":"Intermittent exposure to whole cigarette smoke alters the differentiation of primary small airway epithelial cells in the air-liquid interface culture","volume":"10","author":"Gindele","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Rigden, H.M., Alias, A., Havelock, T., O\u2019Donnell, R., Djukanovic, R., Davies, D.E., and Wilson, S.J. (2016). Squamous Metaplasia Is Increased in the Bronchial Epithelium of Smokers with Chronic Obstructive Pulmonary Disease. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0156009"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.1164\/rccm.201408-1492PP","article-title":"Airway basal cells. The \u201csmoking gun\u201d of chronic obstructive pulmonary disease","volume":"190","author":"Crystal","year":"2014","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"251S","DOI":"10.1378\/chest.117.5_suppl_1.251S","article-title":"Comparison of the structural and inflammatory features of COPD and asthma Giles F. Filley Lecture","volume":"117","author":"Jeffery","year":"2000","journal-title":"Chest"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1164\/ajrccm.161.3.9907080","article-title":"Goblet cell hyperplasia and epithelial inflammation in peripheral airways of smokers with both symptoms of chronic bronchitis and chronic airflow limitation","volume":"161","author":"Saetta","year":"2000","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1093\/toxsci\/kfy226","article-title":"Evaluating Mode of Action of Acrolein Toxicity in an In Vitro Human Airway Tissue Model","volume":"166","author":"Xiong","year":"2018","journal-title":"Toxicol. Sci."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1016\/j.envpol.2019.03.118","article-title":"Combined cytotoxicity of co-exposure to aldehyde mixtures on human bronchial epithelial BEAS-2B cells","volume":"250","author":"Zhang","year":"2019","journal-title":"Environ. Pollut."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1021\/tx5001046","article-title":"Molecular mechanisms of aldehyde toxicity: A chemical perspective","volume":"27","author":"LoPachin","year":"2014","journal-title":"Chem. Res. Toxicol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"25306","DOI":"10.1007\/s11356-018-2584-z","article-title":"Combined effects of co-exposure to formaldehyde and acrolein mixtures on cytotoxicity and genotoxicity in vitro","volume":"25","author":"Zhang","year":"2018","journal-title":"Environ. Sci. Pollut. Res. Int."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"125482","DOI":"10.1016\/j.chemosphere.2019.125482","article-title":"Combined cell death of co-exposure to aldehyde mixtures on human bronchial epithelial BEAS-2B cells: Molecular insights into the joint action","volume":"244","author":"Zhang","year":"2020","journal-title":"Chemosphere"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1093\/toxsci\/kfv122","article-title":"Impact Assessment of Cigarette Smoke Exposure on Organotypic Bronchial Epithelial Tissue Cultures: A Comparison of Mono-Culture and Coculture Model Containing Fibroblasts","volume":"147","author":"Iskandar","year":"2015","journal-title":"Toxicol. Sci."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1159\/000506833","article-title":"Modulation of Airway Epithelial Innate Immunity and Wound Repair by M(GM-CSF) and M(M-CSF) Macrophages","volume":"12","author":"Vandeghinste","year":"2020","journal-title":"J. Innate Immun."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.tiv.2018.10.001","article-title":"Multi-omics analysis: Repeated exposure of a 3D bronchial tissue culture to whole-cigarette smoke","volume":"54","author":"Ishikawa","year":"2019","journal-title":"Toxicol. Vitro"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"18880","DOI":"10.1073\/pnas.1005574107","article-title":"Autophagy protein microtubule-associated protein 1 light chain-3B (LC3B) activates extrinsic apoptosis during cigarette smoke-induced emphysema","volume":"107","author":"Chen","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"153083","DOI":"10.1016\/j.tox.2021.153083","article-title":"Toxicity mechanism of acrolein on DNA damage and apoptosis in BEAS-2B cells: Insights from cell biology and molecular docking analyses","volume":"466","author":"Liu","year":"2022","journal-title":"Toxicology"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1021\/acs.chemrestox.0c00350","article-title":"Coexposure to Inhaled Aldehydes or Carbon Dioxide Enhances the Carcinogenic Properties of the Tobacco-Specific Nitrosamine 4-Methylnitrosamino-1-(3-pyridyl)-1-butanone in the A\/J Mouse Lung","volume":"34","author":"Peterson","year":"2021","journal-title":"Chem. Res. Toxicol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/21\/3481\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:09:58Z","timestamp":1760144998000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/21\/3481"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,3]]},"references-count":104,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["cells11213481"],"URL":"https:\/\/doi.org\/10.3390\/cells11213481","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,3]]}}}