{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T16:10:55Z","timestamp":1788883855906,"version":"build-2803163510"},"reference-count":108,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2020,9,27]],"date-time":"2020-09-27T00:00:00Z","timestamp":1601164800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Chinese Major Scientific and Technological Special Project for Major New Drug Creation","award":["No. 2017ZX09201002-006"],"award-info":[{"award-number":["No. 2017ZX09201002-006"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Chronic obstructive pulmonary disease (COPD) is associated with high morbidity and mortality globally. Studies show that airway mucus hypersecretion strongly compromises lung function, leading to frequent hospitalization and mortality, highlighting an urgent need for effective COPD treatments. MUC5AC is known to contribute to severe muco-obstructive lung diseases, worsening COPD pathogenesis. Various pathways are implicated in the aberrant MUC5AC production and secretion MUC5AC. These include signaling pathways associated with mucus-secreting cell differentiation [nuclear factor-\u03baB (NF-\u03baB)and IL-13-STAT6- SAM pointed domain containing E26 transformation-specific transcription factor (SPDEF), as well as epithelial sodium channel (ENaC) and cystic fibrosis transmembrane conductance regulator (CFTR)], and signaling pathways related to mucus transport and excretion-ciliary beat frequency (CBF). Various inhibitors of mucus hypersecretion are in clinical use but have had limited benefits against COPD. Thus, novel therapies targeting airway mucus hypersecretion should be developed for effective management of muco-obstructive lung disease. Here, we systematically review the mechanisms and pathogenesis of airway mucus hypersecretion, with emphasis on multi-target and multi-link intervention strategies for the elucidation of novel inhibitors of airway mucus hypersecretion.<\/jats:p>","DOI":"10.3390\/molecules25194437","type":"journal-article","created":{"date-parts":[[2020,9,28]],"date-time":"2020-09-28T10:39:58Z","timestamp":1601289598000},"page":"4437","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["The Potential Role and Regulatory Mechanisms of MUC5AC in Chronic Obstructive Pulmonary Disease"],"prefix":"10.3390","volume":"25","author":[{"given":"Jingyuan","family":"Li","sequence":"first","affiliation":[{"name":"Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuguang","family":"Ye","sequence":"additional","affiliation":[{"name":"Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China"},{"name":"Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,27]]},"reference":[{"key":"ref_1","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":"New Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1706","DOI":"10.1016\/S0140-6736(18)30841-9","article-title":"Prevalence and risk factors of chronic obstructive pulmonary disease in China (the China Pulmonary Health [CPH] study): A national cross-sectional study","volume":"391","author":"Wang","year":"2018","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"18942","DOI":"10.1038\/s41598-019-55405-2","article-title":"Tensin1 expression and function in chronic obstructive pulmonary disease","volume":"9","author":"Stylianou","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1941","DOI":"10.1056\/NEJMra1813799","article-title":"Muco-Obstructive Lung Diseases","volume":"380","author":"Boucher","year":"2019","journal-title":"New Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1465-9921-10-1","article-title":"BODE index versus GOLD classification for explaining anxious and depressive symptoms in patients with COPD\u2014A cross-sectional study","volume":"10","author":"Funk","year":"2009","journal-title":"Respir. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1183\/09031936.00127809","article-title":"Tiotropium as a first maintenance drug in COPD: Secondary analysis of the UPLIFT trial","volume":"36","author":"Troosters","year":"2010","journal-title":"Eur. Respir. J."},{"key":"ref_7","first-page":"CD012066","article-title":"Long-acting muscarinic antagonist (LAMA) plus long-acting beta-agonist (LABA) versus LABA plus inhaled corticosteroid (ICS) for stable chronic obstructive pulmonary disease (COPD)","volume":"2","author":"Horita","year":"2017","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.1056\/NEJMoa1713901","article-title":"Once-Daily Single-Inhaler Triple versus Dual Therapy in Patients with COPD","volume":"378","author":"Lipson","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1016\/j.chest.2018.06.022","article-title":"POINT: Should LAMA\/LABA Combination Therapy Be Used as Initial Maintenance Treatment for COPD? Yes","volume":"154","author":"Cazzola","year":"2018","journal-title":"Chest"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2222","DOI":"10.1056\/NEJMoa1516385","article-title":"Indacaterol-Glycopyrronium versus Salmeterol-Fluticasone for COPD","volume":"374","author":"Wedzicha","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e56","DOI":"10.1164\/rccm.202003-0625ST","article-title":"Pharmacologic Management of Chronic Obstructive Pulmonary Disease. An Official American Thoracic Society Clinical Practice Guideline","volume":"201","author":"Nici","year":"2020","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"k4388","DOI":"10.1136\/bmj.k4388","article-title":"Triple therapy in the management of chronic obstructive pulmonary disease: Systematic review and meta-analysis","volume":"363","author":"Zheng","year":"2018","journal-title":"BMJ"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1016\/j.chest.2018.12.016","article-title":"Adding a LAMA to ICS\/LABA Therapy: A Meta-analysis of Triple Combination Therapy in COPD","volume":"155","author":"Calzetta","year":"2019","journal-title":"Chest"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1801586","DOI":"10.1183\/13993003.01586-2018","article-title":"Triple therapy versus single and dual long-acting bronchodilator therapy in COPD: A systematic review and meta-analysis","volume":"52","author":"Cazzola","year":"2018","journal-title":"Eur. Respir. J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1136\/thoraxjnl-2018-213035","article-title":"Building toolkits for COPD exacerbations: Lessons from the past and present","volume":"74","author":"Sapey","year":"2019","journal-title":"Thorax"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.3348\/kjr.2018.0724","article-title":"Clinical Utility of Quantitative CT Analysis for Fissure Completeness in Bronchoscopic Lung Volume Reduction: Comparison between CT and Chartis\u2122","volume":"20","author":"Lee","year":"2019","journal-title":"Korean J. Radiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1164\/rccm.200612-1772OC","article-title":"Survival after lung volume reduction in chronic obstructive pulmonary disease: Insights from small airway pathology","volume":"176","author":"Hogg","year":"2007","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1165\/rcmb.2017-0072TR","article-title":"Epigenetics of Mucus Hypersecretion in Chronic Respiratory Diseases","volume":"58","author":"Saco","year":"2018","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"L334","DOI":"10.1152\/ajplung.00059.2016","article-title":"Targeted epigenetic editing of SPDEF reduces mucus production in lung epithelial cells","volume":"312","author":"Song","year":"2017","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"L1042","DOI":"10.1152\/ajplung.00418.2015","article-title":"Autophagy plays an essential role in cigarette smoke-induced expression of MUC5AC in airway epithelium","volume":"310","author":"Zhou","year":"2016","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1442","DOI":"10.1038\/mi.2016.27","article-title":"The innate immune properties of airway mucosal surfaces are regulated by dynamic interactions between mucins and interacting proteins: The mucin interactome","volume":"9","author":"Radicioni","year":"2016","journal-title":"Mucosal Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"L82","DOI":"10.1152\/ajplung.00049.2019","article-title":"MUC1 contributes to goblet cell metaplasia and MUC5AC expression in response to cigarette smoke in vivo","volume":"319","author":"Kato","year":"2020","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1579","DOI":"10.1016\/j.stemcr.2018.03.013","article-title":"Single-Cell Transcriptomic Profiling of Pluripotent Stem Cell-Derived SCGB3A2+ Airway Epithelium","volume":"10","author":"McCauley","year":"2018","journal-title":"Stem Cell Rep."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Mihalj, M., Bujak, M., Butkovi\u0107, J., Zub\u010di\u0107, \u017d., Tolu\u0161i\u0107 Levak, M., \u010ces, J., Kopi\u0107, V., Baus Lon\u010dar, M., and Mihalj, H. (2019). Differential Expression of TFF1 and TFF3 in Patients Suffering from Chronic Rhinosinusitis with Nasal Polyposis. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20215461"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1465-9921-9-1","article-title":"Clara cell adhesion and migration to extracellular matrix","volume":"9","author":"Atkinson","year":"2008","journal-title":"Respir. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1038\/s41598-019-39079-4","article-title":"Increase in secreted airway mucins and partial Muc5b STAT6\/FoxA2 regulation during Pneumocystis primary infection","volume":"9","author":"Rojas","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"16761","DOI":"10.1038\/s41598-017-17037-2","article-title":"Imaging viscosity of intragranular mucin matrix in cystic fibrosis cells","volume":"7","author":"Requena","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"161","DOI":"10.3342\/ceo.2012.5.3.161","article-title":"Phorbol 12-Myristate 13-Acetate Induces MUC16 Expression via PKC\u03b4 and p38 in Human Airway Epithelial Cells","volume":"5","author":"Bae","year":"2012","journal-title":"Clin. Exp. Otorhinolaryngol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1097\/MLG.0b013e3180383651","article-title":"Upper airway mucin gene expression: A review","volume":"117","author":"Ali","year":"2007","journal-title":"Laryngoscope"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1152\/physrev.00010.2005","article-title":"Respiratory tract mucin genes and mucin glycoproteins in health and disease","volume":"86","author":"Rose","year":"2006","journal-title":"Physiol. Rev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1111\/j.1440-1827.2011.02734.x","article-title":"Mucins in human neoplasms: Clinical pathology, gene expression and diagnostic application","volume":"61","author":"Yonezawa","year":"2011","journal-title":"Pathol. Int."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"393","DOI":"10.3892\/ol.2016.4672","article-title":"Differential expression of mucins in Middle Eastern patients with colorectal cancer","volume":"12","author":"Abdulla","year":"2016","journal-title":"Oncol. Lett."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1038\/nrc2761","article-title":"Mucins in cancer: Function, prognosis and therapy","volume":"9","author":"Kufe","year":"2009","journal-title":"Nat. Rev. Cancer"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1165\/rcmb.2005-0436SF","article-title":"Airway mucus: From production to secretion","volume":"34","author":"Williams","year":"2006","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1155\/2006\/901417","article-title":"Mucin overproduction in chronic inflammatory lung disease","volume":"13","author":"Hauber","year":"2006","journal-title":"Can. Respir. J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"980","DOI":"10.1016\/j.ijporl.2010.05.009","article-title":"Extending the chinchilla middle ear epithelial model for mucin gene investigation","volume":"74","author":"Kerschner","year":"2010","journal-title":"Int. J. Pediatr. Otorhinolaryngol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1186\/s12931-015-0247-x","article-title":"Altered protease and antiprotease balance during a COPD exacerbation contributes to mucus obstruction","volume":"16","author":"Chillappagari","year":"2015","journal-title":"Respir. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1165\/rcmb.2005-0460OC","article-title":"Central role of Muc5ac expression in mucous metaplasia and its regulation by conserved 5\u2032 elements","volume":"37","author":"Young","year":"2007","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1186\/1465-9921-7-79","article-title":"Long-term clearance from small airways in subjects with ciliary dysfunction","volume":"7","author":"Falk","year":"2006","journal-title":"Respir. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1186\/1465-9921-12-59","article-title":"IL-4 and IL-13 exposure during mucociliary differentiation of bronchial epithelial cells increases antimicrobial activity and expression of antimicrobial peptides","volume":"12","author":"Zuyderduyn","year":"2011","journal-title":"Respir. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1016\/j.stemcr.2016.09.010","article-title":"Rare SOX2+ Airway Progenitor Cells Generate KRT5+ Cells that Repopulate Damaged Alveolar Parenchyma following Influenza Virus Infection","volume":"7","author":"Ray","year":"2016","journal-title":"Stem Cell Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.clim.2013.12.003","article-title":"Airway epithelial regulation of pulmonary immune homeostasis and inflammation","volume":"151","author":"Hallstrand","year":"2014","journal-title":"Clin. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e49248","DOI":"10.7554\/eLife.49248","article-title":"ENaC-mediated sodium influx exacerbates NLRP3-dependent inflammation in cystic fibrosis","volume":"8","author":"Scambler","year":"2019","journal-title":"eLife"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1111\/j.1476-5381.2010.00747.x","article-title":"ENaC-mediated effects assessed by MRI in a rat model of hypertonic saline-induced lung hydration","volume":"160","author":"Cannet","year":"2010","journal-title":"Br. J. Pharmacol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"109578","DOI":"10.1016\/j.jbiomech.2019.109578","article-title":"Muco-ciliary clearance: A review of modelling techniques","volume":"99","author":"Vanaki","year":"2020","journal-title":"J. Biomech."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1089\/dna.2013.2079","article-title":"Rhythmic pressure waves induce mucin5AC expression via an EGFR-mediated signaling pathway in human airway epithelial cells","volume":"32","author":"Liu","year":"2013","journal-title":"DNA Cell Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1165\/rcmb.2006-0082SF","article-title":"Effective mucus clearance is essential for respiratory health","volume":"35","author":"Randell","year":"2006","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"C16","DOI":"10.1152\/ajpcell.00341.2018","article-title":"Oxidative stress, autophagy and airway ion transport","volume":"316","year":"2019","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1002\/alr.21878","article-title":"Myrtol standardized affects mucociliary clearance","volume":"7","author":"Li","year":"2017","journal-title":"Int. Forum Allergy Rhinol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2243","DOI":"10.1111\/j.1476-5381.2012.01929.x","article-title":"Roflumilast N-oxide, a PDE4 inhibitor, improves cilia motility and ciliated human bronchial epithelial cells compromised by cigarette smoke in vitro","volume":"166","author":"Milara","year":"2012","journal-title":"Br. J. Pharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1159\/000447668","article-title":"Endoplasmic Reticulum Stress Is a Danger Signal Promoting Innate Inflammatory Responses in Bronchial Epithelial Cells","volume":"8","author":"Lasitschka","year":"2016","journal-title":"J. Innate Immun."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"7349","DOI":"10.1038\/s41598-018-25799-6","article-title":"A novel method for expansion and differentiation of mouse tracheal epithelial cells in culture","volume":"8","author":"Eenjes","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Kogiso, H., Ikeuchi, Y., Sumiya, M., Hosogi, S., Tanaka, S., Shimamoto, C., Inui, T., Marunaka, Y., and Nakahari, T. (2018). Seihai-to (TJ-90)-Induced Activation of Airway Ciliary Beatings of Mice: Ca2+ Modulation of cAMP-Stimulated Ciliary Beatings via PDE. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19030658"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Xu, L., and Jiang, Y. (2019). Mathematical Modeling of Mucociliary Clearance: A Mini-Review. Cells, 8.","DOI":"10.3390\/cells8070736"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1159\/000453594","article-title":"Transmembrane Mucins: Signaling Receptors at the Intersection of Inflammation and Cancer","volume":"9","author":"Strijbis","year":"2017","journal-title":"J. Innate Immun."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1016\/j.bpj.2013.07.050","article-title":"Spatial configuration and composition of charge modulates transport into a mucin hydrogel barrier","volume":"105","author":"Li","year":"2013","journal-title":"Biophys. J."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2109","DOI":"10.1038\/s41598-018-20444-8","article-title":"ATP12A promotes mucus dysfunction during Type 2 airway inflammation","volume":"8","author":"Lennox","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/1465-9921-6-38","article-title":"Association of current smoking with airway inflammation in chronic obstructive pulmonary disease and asymptomatic smokers","volume":"6","author":"Willemse","year":"2005","journal-title":"Respir. Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1610","DOI":"10.1128\/IAI.03073-14","article-title":"The levels of Brachyspira hyodysenteriae binding to porcine colonic mucins differ between individuals, and binding is increased to mucins from infected pigs with de novo MUC5AC synthesis","volume":"83","author":"Mahu","year":"2015","journal-title":"Infect. Immun."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1093\/carcin\/bgx039","article-title":"Muc1 knockout potentiates murine lung carcinogenesis involving an epiregulin-mediated EGFR activation feedback loop","volume":"38","author":"Xu","year":"2017","journal-title":"Carcinogenesis"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1093\/glycob\/cwu092","article-title":"Cystic fibrosis and bacterial colonization define the sputum N-glycosylation phenotype","volume":"25","author":"Venkatakrishnan","year":"2015","journal-title":"Glycobiology"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1111\/j.1469-0691.2006.01396.x","article-title":"Should patients with acute exacerbation of chronic bronchitis be treated with antibiotics? Advantages of the use of fluoroquinolones","volume":"12","author":"Mensa","year":"2006","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.pupt.2014.09.008","article-title":"Luteolin inhibited the gene expression, production and secretion of MUC5AC mucin via regulation of nuclear factor kappa B signaling pathway in human airway epithelial cells","volume":"31","author":"Lee","year":"2015","journal-title":"Pulm. Pharmacol. Ther."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.intimp.2016.08.002","article-title":"S-allylmercapto-l-cysteine modulates MUC5AC and AQP5 secretions in a COPD model via NF-\u03baB signaling pathway","volume":"39","author":"Yang","year":"2016","journal-title":"Int. Immunopharmacol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1136\/thoraxjnl-2014-205731","article-title":"Tiotropium attenuates IL-13-induced goblet cell metaplasia of human airway epithelial cells","volume":"70","author":"Kistemaker","year":"2015","journal-title":"Thorax"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"L22","DOI":"10.1152\/ajplung.00163.2014","article-title":"Linking increased airway hydration, ciliary beating, and mucociliary clearance through ENaC inhibition","volume":"308","author":"Hemmerling","year":"2015","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1165\/rcmb.2016-0226OC","article-title":"The Cystic Fibrosis Transmembrane Conductance Regulator Potentiator Ivacaftor Augments Mucociliary Clearance Abrogating Cystic Fibrosis Transmembrane Conductance Regulator Inhibition by Cigarette Smoke","volume":"56","author":"Raju","year":"2017","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.2174\/0929867311320120004","article-title":"Pharmacological and dietary antioxidant therapies for chronic obstructive pulmonary disease","volume":"20","author":"Biswas","year":"2013","journal-title":"Curr. Med. Chem."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.phrs.2004.07.006","article-title":"Effects of salmeterol on cilia and mucus in COPD and pneumonia patients","volume":"51","author":"Piatti","year":"2005","journal-title":"Pharmacol. Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"16785","DOI":"10.1038\/s41598-019-53278-z","article-title":"Upregulation of caveolin-1 and its colocalization with cytokine receptors contributes to beta cell apoptosis","volume":"9","author":"Bae","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Tsai, Y.C., Wang, S.L., Wu, M.Y., Liao, C.H., Lin, C.H., Chen, J.J., Fu, S.L., and Pilloin, A. (2018). Flavonoid Isolated from Aquilaria sinensis, Exhibits Anti-Inflammatory Activity In Vitro and In Vivo. Molecules, 23.","DOI":"10.3390\/molecules23123177"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.phymed.2018.01.012","article-title":"Piscroside C inhibits TNF-\u03b1\/NF-\u03baB pathway by the suppression of PKC\u03b4 activity for TNF-RSC formation in human airway epithelial cells","volume":"40","author":"Lee","year":"2018","journal-title":"Phytomedicine"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.cyto.2015.08.262","article-title":"Verproside inhibits TNF-\u03b1-induced MUC5AC expression through suppression of the TNF-\u03b1\/NF-\u03baB pathway in human airway epithelial cells","volume":"77","author":"Lee","year":"2016","journal-title":"Cytokine"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1016\/j.bbrc.2018.03.206","article-title":"Resistin upregulates MUC5AC\/B mucin gene expression in human airway epithelial cells","volume":"499","author":"Kwak","year":"2018","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Cheng, X.H., Black, M., Ustiyan, V., Le, T., Fulford, L., Sridharan, A., Medvedovic, M., Kalinichenko, V.V., Whitsett, J.A., and Kalin, T.V. (2014). SPDEF inhibits prostate carcinogenesis by disrupting a positive feedback loop in regulation of the Foxm1 oncogene. PLoS Genet., 10.","DOI":"10.1371\/journal.pgen.1004656"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1172\/JCI29176","article-title":"SPDEF regulates goblet cell hyperplasia in the airway epithelium","volume":"117","author":"Park","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"S98","DOI":"10.1513\/AnnalsATS.201711-868MG","article-title":"Interleukin-13 Stimulation Reveals the Cellular and Functional Plasticity of the Airway Epithelium","volume":"15","author":"Seibold","year":"2018","journal-title":"Ann. Am. Thorac. Soc."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"eaai8583","DOI":"10.1126\/scisignal.aai8583","article-title":"The FOXM1 inhibitor RCM-1 suppresses goblet cell metaplasia and prevents IL-13 and STAT6 signaling in allergen-exposed mice","volume":"10","author":"Sun","year":"2017","journal-title":"Sci. Signal."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"2013","DOI":"10.1016\/S0140-6736(08)60869-7","article-title":"Effect of carbocisteine on acute exacerbation of chronic obstructive pulmonary disease (PEACE Study): A randomised placebo-controlled study","volume":"371","author":"Zheng","year":"2008","journal-title":"Lancet"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1186\/s12931-019-1170-3","article-title":"Reduced expression of the Ion channel CFTR contributes to airspace enlargement as a consequence of aging and in response to cigarette smoke in mice","volume":"20","author":"Wellmerling","year":"2019","journal-title":"Respir. Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"190068","DOI":"10.1183\/16000617.0068-2019","article-title":"CFTR targeted therapies: Recent advances in cystic fibrosis and possibilities in other diseases of the airways","volume":"29","author":"Patel","year":"2020","journal-title":"Eur. Respir. Rev."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1080\/17476348.2018.1475235","article-title":"CFTR dysfunction in cystic fibrosis and chronic obstructive pulmonary disease","volume":"12","author":"Fernandez","year":"2018","journal-title":"Expert Rev. Respir. Med."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1136\/thoraxjnl-2011-201183","article-title":"Significance of the microbiome in obstructive lung disease","volume":"67","author":"Han","year":"2012","journal-title":"Thorax"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1590","DOI":"10.1183\/09031936.00076214","article-title":"Deleterious impact of Pseudomonas aeruginosa on cystic fibrosis transmembrane conductance regulator function and rescue in airway epithelial cells","volume":"45","author":"Trinh","year":"2015","journal-title":"Eur. Respir. J."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1007\/s00424-018-2160-x","article-title":"Expression and function of Anoctamin 1\/TMEM16A calcium-activated chloride channels in airways of in vivo mouse models for cystic fibrosis research","volume":"470","author":"Hahn","year":"2018","journal-title":"Pflugers Arch."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1007\/s10157-011-0506-1","article-title":"Proteolytic activation of the epithelial sodium channel and therapeutic application of a serine protease inhibitor for the treatment of salt-sensitive hypertension","volume":"16","author":"Kitamura","year":"2012","journal-title":"Clin. Exp. Nephrol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"3216","DOI":"10.1073\/pnas.1010334108","article-title":"Deletion of the ubiquitin ligase Nedd4L in lung epithelia causes cystic fibrosis-like disease","volume":"108","author":"Kimura","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.jphs.2019.01.011","article-title":"Auto-measure emphysematous parameters and pathophysiological gene expression profiles in experimental mouse models of acute and chronic obstructive pulmonary diseases","volume":"140","author":"Nakashima","year":"2019","journal-title":"J. Pharmacol. Sci."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"3259","DOI":"10.2147\/DDDT.S198874","article-title":"Carbocisteine inhibits the expression of Muc5b in COPD mouse model","volume":"13","author":"Song","year":"2019","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1164\/rccm.201802-0245OC","article-title":"An Improved Inhaled Mucolytic to Treat Airway Muco-obstructive Diseases","volume":"199","author":"Ehre","year":"2019","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"13896","DOI":"10.1038\/s41598-019-50356-0","article-title":"NRF2-dependent gene expression promotes ciliogenesis and Hedgehog signaling","volume":"9","author":"Blanco","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"G1022","DOI":"10.1152\/ajpgi.00033.2020","article-title":"HDAC6-dependent ciliophagy is involved in ciliary loss and cholangiocarcinoma growth in human cells and murine models","volume":"318","author":"Peixoto","year":"2020","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"5212","DOI":"10.1172\/JCI69636","article-title":"Histone deacetylase 6-mediated selective autophagy regulates COPD-associated cilia dysfunction","volume":"123","author":"Lam","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"3016","DOI":"10.1002\/ptr.6413","article-title":"Obtusifolin isolated from the seeds of Cassia obtusifolia regulates the gene expression and production of MUC5AC mucin in airway epithelial cells via affecting NF-kB pathway","volume":"33","author":"Choi","year":"2019","journal-title":"Phytother. Res."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1002\/ptr.5334","article-title":"The Flavonoid 7,4\u2032-Dihydroxyflavone Inhibits MUC5AC Gene Expression, Production, and Secretion via Regulation of NF-\u03baB, STAT6, and HDAC","volume":"29","author":"Liu","year":"2015","journal-title":"Phytother. Res."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.phymed.2013.10.004","article-title":"Effects of the root of Platycodon grandiflorum on airway mucin hypersecretion in vivo and platycodin D(3) and deapi-platycodin on production and secretion of airway mucin in vitro","volume":"21","author":"Ryu","year":"2014","journal-title":"Phytomedicine"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1056\/NEJMoa1700228","article-title":"Tiotropium in Early-Stage Chronic Obstructive Pulmonary Disease","volume":"377","author":"Zhou","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1165\/rcmb.2013-0228OC","article-title":"Cystic fibrosis transmembrane conductance regulator activation by roflumilast contributes to therapeutic benefit in chronic bronchitis","volume":"50","author":"Lambert","year":"2014","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1164\/rccm.201906-1219OC","article-title":"Airway Mucus Hyperconcentration in Non-Cystic Fibrosis Bronchiectasis","volume":"201","author":"Ramsey","year":"2020","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/S2213-2600(13)70286-8","article-title":"Twice daily N-acetylcysteine 600 mg for exacerbations of chronic obstructive pulmonary disease (PANTHEON): A randomised, double-blind placebo-controlled trial","volume":"2","author":"Zheng","year":"2014","journal-title":"Lancet Respir. Med."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1186\/s12931-017-0647-1","article-title":"A 28-day, randomized, double-blind, placebo-controlled, parallel group study of nebulized revefenacin in patients with chronic obstructive pulmonary disease","volume":"18","author":"Pudi","year":"2017","journal-title":"Respir. Res."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1016\/j.rmed.2011.02.007","article-title":"Effects of formoterol and tiotropium bromide on mucus clearance in patients with COPD","volume":"105","author":"Meyer","year":"2011","journal-title":"Respir. Med."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"116485","DOI":"10.1016\/j.lfs.2019.05.041","article-title":"Natural inhibitors on airway mucin: Molecular insight into the therapeutic potential targeting MUC5AC expression and production","volume":"231","author":"Samsuzzaman","year":"2019","journal-title":"Life Sci."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1080\/13543784.2017.1264388","article-title":"Muscarinic antagonists in early stage clinical development for the treatment of asthma","volume":"26","author":"Albertson","year":"2017","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.ejphar.2005.12.072","article-title":"Anticholinergic agents in asthma and COPD","volume":"533","author":"Gross","year":"2006","journal-title":"Eur. J. Pharmacol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1186\/s12931-015-0294-3","article-title":"Roflumilast partially reverses smoke-induced mucociliary dysfunction","volume":"16","author":"Schmid","year":"2015","journal-title":"Respir. Res."},{"key":"ref_107","first-page":"327","article-title":"Effectiveness and safety of hypertonic saline inhalation combined with exercise training in patients with chronic obstructive pulmonary disease: A randomized trial","volume":"54","author":"Valderramas","year":"2009","journal-title":"Respir. Care"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1111\/resp.13047","article-title":"Mucoactive agents for chronic, non-cystic fibrosis lung disease: A systematic review and meta-analysis","volume":"22","author":"Tarrant","year":"2017","journal-title":"Respirology"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/19\/4437\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:14:09Z","timestamp":1760177649000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/19\/4437"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,27]]},"references-count":108,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2020,10]]}},"alternative-id":["molecules25194437"],"URL":"https:\/\/doi.org\/10.3390\/molecules25194437","relation":{"has-preprint":[{"id-type":"doi","id":"10.20944\/preprints202008.0260.v1","asserted-by":"object"}]},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9,27]]}}}