{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T12:03:54Z","timestamp":1792065834788,"version":"4.4.0"},"reference-count":122,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2013,2,1]],"date-time":"2013-02-01T00:00:00Z","timestamp":1359676800000},"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":[[2013,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Chronic bronchitis (CB) is a common but variable phenomenon in chronic obstructive pulmonary disease (COPD). It has numerous clinical consequences, including an accelerated decline in lung function, greater risk of the development of airflow obstruction in smokers, a predisposition to lower respiratory tract infection, higher exacerbation frequency, and worse overall mortality. CB is caused by overproduction and hypersecretion of mucus by goblet cells, which leads to worsening airflow obstruction by luminal obstruction of small airways, epithelial remodeling, and alteration of airway surface tension predisposing to collapse. Despite its clinical sequelae, little is known about the pathophysiology of CB and goblet cell hyperplasia in COPD, and treatment options are limited. In addition, it is becoming increasingly apparent that in the classic COPD spectrum, with emphysema on one end and CB on the other, most patients lie somewhere in the middle. It is known now that many patients with severe emphysema can develop CB, and small airway pathology has been linked to worse clinical outcomes, such as increased mortality and lesser improvement in lung function after lung volume reduction surgery. However, in recent years, a greater understanding of the importance of CB as a phenotype to identify patients with a beneficial response to therapy has been described. Herein we review the epidemiology of CB, the evidence behind its clinical consequences, the current understanding of the pathophysiology of goblet cell hyperplasia in COPD, and current therapies for CB.<\/jats:p>","DOI":"10.1164\/rccm.201210-1843ci","type":"journal-article","created":{"date-parts":[[2012,11,30]],"date-time":"2012-11-30T02:51:50Z","timestamp":1354243910000},"page":"228-237","source":"Crossref","is-referenced-by-count":436,"title":["Chronic Bronchitis and Chronic Obstructive Pulmonary Disease"],"prefix":"10.1093","volume":"187","author":[{"given":"Victor","family":"Kim","sequence":"first","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerard J.","family":"Criner","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2013,2,1]]},"reference":[{"key":"2026032100521305400_bib1","author":"Mathers"},{"key":"2026032100521305400_bib2"},{"key":"2026032100521305400_bib3","doi-asserted-by":"crossref","first-page":"1530","DOI":"10.1164\/ajrccm.153.5.8630597","article-title":"Association of chronic mucus hypersecretion with FEV1 decline and chronic obstructive pulmonary disease morbidity. Copenhagen City Heart Study Group","volume":"153","author":"Vestbo","year":"1996","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032100521305400_bib4","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1378\/chest.08-2062","article-title":"Cough and sputum production are associated with frequent exacerbations and hospitalizations in COPD subjects","volume":"135","author":"Burgel","year":"2009","journal-title":"Chest"},{"key":"2026032100521305400_bib5","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1136\/thx.2008.110619","article-title":"Chronic bronchitis before age 50 years predicts incident airflow limitation and mortality risk","volume":"64","author":"Guerra","year":"2009","journal-title":"Thorax"},{"key":"2026032100521305400_bib6","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1378\/chest.10-2948","article-title":"The chronic bronchitic phenotype of COPD: an analysis of the COPDGene study","volume":"140","author":"Kim","year":"2011","journal-title":"Chest"},{"key":"2026032100521305400_bib7","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1111\/j.1365-2796.1989.tb01349.x","article-title":"Chronic obstructive lung disease in Copenhagen: cross-sectional epidemiological aspects","volume":"226","author":"Lange","year":"1989","journal-title":"J Intern Med"},{"key":"2026032100521305400_bib8","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1016\/S0954-6111(99)90265-2","article-title":"Increasing prevalence of asthma but not of chronic bronchitis in Finland? Report from the FinEsS-Helsinki Study","volume":"93","author":"Pallasaho","year":"1999","journal-title":"Respir Med"},{"key":"2026032100521305400_bib9","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/S0300-2896(15)30272-6","article-title":"Epidemiological study of chronic obstructive pulmonary disease in Spain (IBERPOC): prevalence of chronic respiratory symptoms and airflow limitation","volume":"35","author":"Sobradillo","year":"1999","journal-title":"Arch Bronconeumol"},{"key":"2026032100521305400_bib10","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1053\/rmed.1999.0715","article-title":"Airway obstruction in relation to symptoms in chronic respiratory disease\u2013a nationally representative population study","volume":"94","author":"von Hertzen","year":"2000","journal-title":"Respir Med"},{"key":"2026032100521305400_bib11","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1183\/09031936.01.00087101","article-title":"Variations in the prevalence across countries of chronic bronchitis and smoking habits in young adults","volume":"18","author":"Cerveri","year":"2001","journal-title":"Eur Respir J"},{"key":"2026032100521305400_bib12","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1183\/09031936.01.00098701","article-title":"Determinants of cough in young adults participating in the European Community Respiratory Health Survey","volume":"18","author":"Janson","year":"2001","journal-title":"Eur Respir J"},{"key":"2026032100521305400_bib13","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1183\/09031936.02.00042002","article-title":"Chronic bronchitis among French adults: high prevalence and underdiagnosis","volume":"20","author":"Huchon","year":"2002","journal-title":"Eur Respir J"},{"key":"2026032100521305400_bib14","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1053\/rmed.2003.1446","article-title":"Obstructive Lung Disease in Northern Sweden Studies. Not 15 but 50% of smokers develop COPD?\u2013Report from the Obstructive Lung Disease in Northern Sweden Studies","volume":"97","author":"Lundback","year":"2003","journal-title":"Respir Med"},{"key":"2026032100521305400_bib15","doi-asserted-by":"crossref","first-page":"1973","DOI":"10.1016\/j.rmed.2006.02.024","article-title":"Chronic respiratory symptoms, spirometry and knowledge of COPD among general population","volume":"100","author":"Miravitlles","year":"2006","journal-title":"Respir Med"},{"key":"2026032100521305400_bib16","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1164\/rccm.200603-381OC","article-title":"Incidence of chronic obstructive pulmonary disease in a cohort of young adults according to the presence of chronic cough and phlegm","volume":"175","author":"de Marco","year":"2007","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032100521305400_bib17","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1136\/thx.2009.115725","article-title":"Prevalence of COPD in Spain: impact of undiagnosed COPD on quality of life and daily life activities","volume":"64","author":"Miravitlles","year":"2009","journal-title":"Thorax"},{"key":"2026032100521305400_bib18","first-page":"1052","article-title":"Chronic mucus hypersecretion: prevalence and risk factors in younger individuals","volume":"14","author":"Harmsen","year":"2010","journal-title":"Int J Tuberc Lung Dis"},{"key":"2026032100521305400_bib19","first-page":"A6622","article-title":"Non-obstructive chronic bronchitis in the COPDGene cohort [abstract]","volume":"185","author":"Martinez","year":"2012","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032100521305400_bib20","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1186\/1465-9921-11-122","article-title":"Characterisation of COPD heterogeneity in the ECLIPSE cohort","volume":"11","author":"Agusti","year":"2010","journal-title":"Respir Res"},{"key":"2026032100521305400_bib21","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1183\/09031936.00141611","article-title":"The chronic bronchitis phenotype in subjects with and without COPD: the PLATINO study","volume":"40","author":"de Oca","year":"2012","journal-title":"Eur Respir J"},{"key":"2026032100521305400_bib22","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1378\/chest.130.4.1129","article-title":"Thirty-year cumulative incidence of chronic bronchitis and COPD in relation to 30-year pulmonary function and 40-year mortality: a follow-up in middle-aged rural men","volume":"130","author":"Pelkonen","year":"2006","journal-title":"Chest"},{"key":"2026032100521305400_bib23","article-title":"Trends in COPD (chronic bronchitis and emphysema)","author":"American Lung Association"},{"key":"2026032100521305400_bib24","doi-asserted-by":"crossref","first-page":"S49","DOI":"10.1164\/ajrccm\/140.3_Pt_2.S49","article-title":"Chronic obstructive pulmonary disease mortality in six US cities","volume":"140","author":"Speizer","year":"1989","journal-title":"Am Rev Respir Dis"},{"key":"2026032100521305400_bib25","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1111\/j.1440-1843.2010.01817.x","article-title":"Chronic obstructive pulmonary disease in the absence of chronic bronchitis in China","volume":"15","author":"Lu","year":"2010","journal-title":"Respirology"},{"key":"2026032100521305400_bib26","first-page":"A3736","article-title":"Significance of chronic bronchitis in the COPD CRN Azithromycin in COPD Study [abstract]","volume":"185","author":"Han","year":"2012","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032100521305400_bib27","first-page":"369","article-title":"Predictors of chronic bronchitis in South African adults","volume":"8","author":"Ehrlich","year":"2004","journal-title":"Int J Tuberc Lung Dis"},{"key":"2026032100521305400_bib28","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1183\/09031936.06.00055805","article-title":"Predictors of COPD symptoms: does the sex of the patient matter?","volume":"28","author":"Watson","year":"2006","journal-title":"Eur Respir J"},{"key":"2026032100521305400_bib29","author":"Chapman"},{"key":"2026032100521305400_bib30","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1183\/09031936.03.00094203","article-title":"The occupational burden of chronic obstructive pulmonary disease","volume":"22","author":"Trupin","year":"2003","journal-title":"Eur Respir J"},{"key":"2026032100521305400_bib31","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1136\/thx.2004.035170","article-title":"Biological dust exposure in the workplace is a risk factor for chronic obstructive pulmonary disease","volume":"60","author":"Matheson","year":"2005","journal-title":"Thorax"},{"key":"2026032100521305400_bib32","doi-asserted-by":"crossref","first-page":"1882","DOI":"10.1001\/archinte.1985.00360100152025","article-title":"Respiratory complications of gastroesophageal reflux","volume":"145","author":"Barish","year":"1985","journal-title":"Arch Intern Med"},{"key":"2026032100521305400_bib33","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1378\/chest.108.4.991","article-title":"Chronic cough with a history of excessive sputum production. The spectrum and frequency of causes, key components of the diagnostic evaluation, and outcome of specific therapy","volume":"108","author":"Smyrnios","year":"1995","journal-title":"Chest"},{"key":"2026032100521305400_bib34","first-page":"4","article-title":"The bronchiolar epithelium in cigarette smokers. Observations with the scanning electron microscope","volume":"111","author":"Ebert","year":"1975","journal-title":"Am Rev Respir Dis"},{"key":"2026032100521305400_bib35","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1164\/rccm.200408-1003OC","article-title":"Metalloproteinases mediate mucin 5AC expression by epidermal growth factor receptor activation","volume":"171","author":"Deshmukh","year":"2005","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032100521305400_bib36","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1513\/pats.200502-015AW","article-title":"Acute and chronic airway responses to viral infection: implications for asthma and chronic obstructive pulmonary disease","volume":"2","author":"Holtzman","year":"2005","journal-title":"Proc Am Thorac Soc"},{"key":"2026032100521305400_bib37","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1136\/thx.2003.018879","article-title":"Roles of epidermal growth factor receptor activation in epithelial cell repair and mucin production in airway epithelium","volume":"59","author":"Burgel","year":"2004","journal-title":"Thorax"},{"key":"2026032100521305400_bib38","doi-asserted-by":"crossref","first-page":"2645","DOI":"10.1056\/NEJMoa032158","article-title":"The nature of small-airway obstruction in chronic obstructive pulmonary disease","volume":"350","author":"Hogg","year":"2004","journal-title":"N Engl J Med"},{"key":"2026032100521305400_bib39","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1164\/ajrccm\/151.3_Pt_1.630","article-title":"Ciliary abnormalities in bronchial epithelium of smokers, ex-smokers, and nonsmokers","volume":"151","author":"Verra","year":"1995","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032100521305400_bib40","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1378\/chest.130.4.1102","article-title":"Epithelial mucin stores are increased in the large airways of smokers with airflow obstruction","volume":"130","author":"Innes","year":"2006","journal-title":"Chest"},{"key":"2026032100521305400_bib41","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":"2026032100521305400_bib42","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1080\/15412550802522445","article-title":"Small airway mucous metaplasia and inflammation in chronic obstructive pulmonary disease","volume":"5","author":"Kim","year":"2008","journal-title":"COPD"},{"key":"2026032100521305400_bib43","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1183\/09031936.00146905","article-title":"Clinical relevance of airway remodelling in airway diseases","volume":"30","author":"James","year":"2007","journal-title":"Eur Respir J"},{"key":"2026032100521305400_bib44","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/0034-5687(70)90015-0","article-title":"The stability of peripheral airways","volume":"8","author":"Macklem","year":"1970","journal-title":"Respir Physiol"},{"key":"2026032100521305400_bib45","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1164\/rccm.200405-659OC","article-title":"Small airway morphometry and improvement in pulmonary function after lung volume reduction surgery","volume":"171","author":"Kim","year":"2005","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032100521305400_bib46","first-page":"A712","article-title":"The effect of small airway pathology on survival following lung volume reduction surgery (LVRS) [abstract]","volume":"3","author":"Sciurba","year":"2006","journal-title":"Proc Am Thorac Soc"},{"key":"2026032100521305400_bib47","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1136\/thx.2004.028043","article-title":"Expression of ErbB receptors and mucins in the airways of long term current smokers","volume":"59","author":"O'Donnell","year":"2004","journal-title":"Thorax"},{"key":"2026032100521305400_bib48","first-page":"274","article-title":"Pathology of chronic bronchitis","volume":"266","author":"Reid","year":"1954","journal-title":"Lancet"},{"key":"2026032100521305400_bib49","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1136\/bmj.291.6504.1235","article-title":"Reassessment of inflammation of airways in chronic bronchitis","volume":"291","author":"Mullen","year":"1985","journal-title":"Br Med J (Clin Res Ed)"},{"key":"2026032100521305400_bib50","doi-asserted-by":"crossref","first-page":"1372","DOI":"10.1378\/chest.06-2194","article-title":"The association between small airway obstruction and emphysema phenotypes in COPD","volume":"131","author":"Kim","year":"2007","journal-title":"Chest"},{"key":"2026032100521305400_bib51","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1172\/JCI5909","article-title":"Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production","volume":"103","author":"Zhu","year":"1999","journal-title":"J Clin Invest"},{"key":"2026032100521305400_bib52","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/S1081-1206(10)62426-X","article-title":"T-cell subsets (Th1 versus Th2)","volume":"85","author":"Romagnani","year":"2000","journal-title":"Ann Allergy Asthma Immunol"},{"key":"2026032100521305400_bib53","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1016\/j.coi.2006.09.008","article-title":"The IL-23\/Th(17) axis: therapeutic targets for autoimmune inflammation","volume":"18","author":"Kikly","year":"2006","journal-title":"Curr Opin Immunol"},{"key":"2026032100521305400_bib54","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1067\/mai.2001.117929","article-title":"IL-17 is increased in asthmatic airways and induces human bronchial fibroblasts to produce cytokines","volume":"108","author":"Molet","year":"2001","journal-title":"J Allergy Clin Immunol"},{"key":"2026032100521305400_bib55","doi-asserted-by":"crossref","first-page":"17036","DOI":"10.1074\/jbc.M210429200","article-title":"Stimulation of airway mucin gene expression by interleukin (IL)-17 through IL-6 paracrine\/autocrine loop","volume":"278","author":"Chen","year":"2003","journal-title":"J Biol Chem"},{"key":"2026032100521305400_bib56","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1136\/thorax.55.2.114","article-title":"Relation of sputum inflammatory markers to symptoms and lung function changes in COPD exacerbations","volume":"55","author":"Bhowmik","year":"2000","journal-title":"Thorax"},{"key":"2026032100521305400_bib57","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1164\/ajrccm\/146.4.855","article-title":"Longitudinal lung function decline in subjects with respiratory symptoms","volume":"146","author":"Sherman","year":"1992","journal-title":"Am Rev Respir Dis"},{"key":"2026032100521305400_bib58","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1136\/thx.45.8.579","article-title":"Relation of ventilatory impairment and of chronic mucus hypersecretion to mortality from obstructive lung disease and from all causes","volume":"45","author":"Lange","year":"1990","journal-title":"Thorax"},{"key":"2026032100521305400_bib59","author":"Vestbo"},{"key":"2026032100521305400_bib60","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1111\/j.1365-2249.2009.03965.x","article-title":"T helper type 17-related cytokine expression is increased in the bronchial mucosa of stable chronic obstructive pulmonary disease patients","volume":"157","author":"Di Stefano","year":"2009","journal-title":"Clin Exp Immunol"},{"key":"2026032100521305400_bib61","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1378\/chest.129.4.879","article-title":"Seven-year cumulative incidence of COPD in an age-stratified general population sample","volume":"129","author":"Lindberg","year":"2006","journal-title":"Chest"},{"key":"2026032100521305400_bib62","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1164\/rccm.200901-0047OC","article-title":"The natural history of chronic airflow obstruction revisited: an analysis of the Framingham offspring cohort","volume":"180","author":"Kohansal","year":"2009","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032100521305400_bib63","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1183\/09031936.95.08081333","article-title":"Chronic mucus hypersecretion in COPD and death from pulmonary infection","volume":"8","author":"Prescott","year":"1995","journal-title":"Eur Respir J"},{"key":"2026032100521305400_bib64","first-page":"A1529","article-title":"Chronic bronchitis is associated with worse survival in advanced emphysema [abstract]","volume":"185","author":"Kim","year":"2012","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032100521305400_bib65","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1136\/thorax.58.5.388","article-title":"Lung function and mortality in the United States: data from the First National Health and Nutrition Examination Survey follow up study","volume":"58","author":"Mannino","year":"2003","journal-title":"Thorax"},{"key":"2026032100521305400_bib66","doi-asserted-by":"crossref","first-page":"S56","DOI":"10.1164\/ajrccm\/140.3_Pt_2.S56","article-title":"Respiratory risk factors and mortality: longitudinal studies in Washington County, Maryland","volume":"140","author":"Tockman","year":"1989","journal-title":"Am Rev Respir Dis"},{"key":"2026032100521305400_bib67","doi-asserted-by":"crossref","first-page":"1608","DOI":"10.1164\/ajrccm.161.5.9908022","article-title":"Time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease","volume":"161","author":"Seemungal","year":"2000","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032100521305400_bib68","first-page":"A3735","article-title":"Chronic bronchitis predicts greater frequency and severity of COPD exacerbations in moderate to severe COPD [abstract]","volume":"185","author":"Kim","year":"2012","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032100521305400_bib69","doi-asserted-by":"crossref","first-page":"114","DOI":"10.3109\/15412555.2011.558546","article-title":"The effect of chronic sputum production on respiratory symptoms in severe COPD","volume":"8","author":"Kim","year":"2011","journal-title":"COPD"},{"key":"2026032100521305400_bib70","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1136\/thx.42.11.843","article-title":"Structure of central airways in current smokers and ex-smokers with and without mucus hypersecretion: relationship to lung function","volume":"42","author":"Mullen","year":"1987","journal-title":"Thorax"},{"key":"2026032100521305400_bib71","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1378\/chest.101.3.607","article-title":"Reversibility of airways injury over a 12-month period following smoking cessation","volume":"101","author":"Swan","year":"1992","journal-title":"Chest"},{"key":"2026032100521305400_bib72","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.4187\/respcare.07521198","article-title":"Conventional chest physical therapy for obstructive lung disease","volume":"52","author":"van der Schans","year":"2007","journal-title":"Respir Care"},{"key":"2026032100521305400_bib73","doi-asserted-by":"crossref","first-page":"859","DOI":"10.4187\/respcare.07520859","article-title":"Mucolytics, expectorants, and mucokinetic medications","volume":"52","author":"Rubin","year":"2007","journal-title":"Respir Care"},{"key":"2026032100521305400_bib74","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1136\/thx.28.6.742","article-title":"A preliminary study of the effect of guaiphenesin on mucociliary clearance from the human lung","volume":"28","author":"Thomson","year":"1973","journal-title":"Thorax"},{"key":"2026032100521305400_bib75","doi-asserted-by":"crossref","first-page":"25803","DOI":"10.1074\/jbc.M604332200","article-title":"Hypertonic saline therapy in cystic fibrosis: evidence against the proposed mechanism involving aquaporins","volume":"281","author":"Levin","year":"2006","journal-title":"J Biol Chem"},{"key":"2026032100521305400_bib76","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.molmed.2007.05.001","article-title":"Cystic fibrosis: a disease of vulnerability to airway surface dehydration","volume":"13","author":"Boucher","year":"2007","journal-title":"Trends Mol Med"},{"key":"2026032100521305400_bib77","doi-asserted-by":"crossref","first-page":"327","DOI":"10.4187\/respcare.09540327","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":"2026032100521305400_bib78","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1164\/ajrccm\/147.5.1132","article-title":"Markers of mucus secretion and DNA levels in induced sputum from asthmatic and from healthy subjects","volume":"147","author":"Fahy","year":"1993","journal-title":"Am Rev Respir Dis"},{"key":"2026032100521305400_bib79","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1378\/chest.113.5.1329","article-title":"Treatment of idiopathic bronchiectasis with aerosolized recombinant human DNase I. rhDNase Study Group","volume":"113","author":"O\u2019Donnell","year":"1998","journal-title":"Chest"},{"key":"2026032100521305400_bib80","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1152\/jappl.1989.66.3.1035","article-title":"Effect of cAMP on ciliary function in rabbit tracheal epithelial cells","volume":"66","author":"Tamaoki","year":"1989","journal-title":"J Appl Physiol"},{"key":"2026032100521305400_bib81","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/0952-0600(92)90068-R","article-title":"The effects of salmeterol and salbutamol on ciliary beat frequency of cultured human bronchial epithelial cells, in vitro","volume":"5","author":"Devalia","year":"1992","journal-title":"Pulm Pharmacol"},{"key":"2026032100521305400_bib82","doi-asserted-by":"crossref","first-page":"S275","DOI":"10.1067\/mai.2002.129412","article-title":"Effects of beta-agonists on airway epithelial cells","volume":"110","author":"Salathe","year":"2002","journal-title":"J Allergy Clin Immunol"},{"key":"2026032100521305400_bib83","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1165\/rcmb.2007-0279RC","article-title":"Chronic exposure to beta-blockers attenuates inflammation and mucin content in a murine asthma model","volume":"38","author":"Nguyen","year":"2008","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026032100521305400_bib84","doi-asserted-by":"crossref","first-page":"2435","DOI":"10.1073\/pnas.0810902106","article-title":"Beta2-adrenoceptor signaling is required for the development of an asthma phenotype in a murine model","volume":"106","author":"Nguyen","year":"2009","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026032100521305400_bib85","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/0002-9343(85)90082-8","article-title":"Effects of methylxanthines on airway mucociliary function","volume":"79","author":"Wanner","year":"1985","journal-title":"Am J Med"},{"key":"2026032100521305400_bib86","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/0007-0971(82)90051-1","article-title":"Sustained-release theophylline in chronic bronchitis","volume":"76","author":"Anderson","year":"1982","journal-title":"Br J Dis Chest"},{"key":"2026032100521305400_bib87","first-page":"747","article-title":"The efficacy of orally administered theophylline, inhaled salbutamol, and a combination of the two as chronic therapy in the management of chronic bronchitis with reversible air-flow obstruction","volume":"131","author":"Taylor","year":"1985","journal-title":"Am Rev Respir Dis"},{"key":"2026032100521305400_bib88","first-page":"227","article-title":"Lung mucociliary function in man: interdependence of bronchial and tracheal mucus transport velocities with lung clearance in bronchial asthma and healthy subjects","volume":"26","author":"Foster","year":"1982","journal-title":"Ann Occup Hyg"},{"key":"2026032100521305400_bib89","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1164\/ajrccm.155.4.9105068","article-title":"Quality of life changes in COPD patients treated with salmeterol","volume":"155","author":"Jones","year":"1997","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032100521305400_bib90","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1378\/chest.115.4.957","article-title":"Efficacy of salmeterol xinafoate in the treatment of COPD","volume":"115","author":"Mahler","year":"1999","journal-title":"Chest"},{"key":"2026032100521305400_bib91","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1378\/chest.129.3.509","article-title":"Effects of tiotropium with and without formoterol on airflow obstruction and resting hyperinflation in patients with COPD","volume":"129","author":"van Noord","year":"2006","journal-title":"Chest"},{"key":"2026032100521305400_bib92","first-page":"503","article-title":"The influence of a new beta agonist: formoterol on mucociliary function","volume":"9","author":"Melloni","year":"1992","journal-title":"Rev Mal Respir"},{"key":"2026032100521305400_bib93","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1513\/pats.2306015","article-title":"Submucosal glands and airway defense","volume":"1","author":"Wine","year":"2004","journal-title":"Proc Am Thorac Soc"},{"key":"2026032100521305400_bib94","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1007\/s00418-008-0455-2","article-title":"The epithelial cholinergic system of the airways","volume":"130","author":"Kummer","year":"2008","journal-title":"Histochem Cell Biol"},{"key":"2026032100521305400_bib95","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/j.pupt.2009.06.002","article-title":"Alternative mechanisms for tiotropium","volume":"22","author":"Bateman","year":"2009","journal-title":"Pulm Pharmacol Ther"},{"key":"2026032100521305400_bib96","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1378\/chest.86.3.387","article-title":"Sputum changes associated with the use of ipratropium bromide","volume":"86","author":"Ghafouri","year":"1984","journal-title":"Chest"},{"key":"2026032100521305400_bib97","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1378\/chest.103.2.488","article-title":"The acute effect of ipratropium bromide bronchodilator therapy on cough clearance in COPD","volume":"103","author":"Bennett","year":"1993","journal-title":"Chest"},{"key":"2026032100521305400_bib98","doi-asserted-by":"crossref","first-page":"1294","DOI":"10.1378\/chest.118.5.1294","article-title":"The spirometric efficacy of once-daily dosing with tiotropium in stable COPD: a 13-week multicenter trial. The US Tiotropium Study Group","volume":"118","author":"Casaburi","year":"2000","journal-title":"Chest"},{"key":"2026032100521305400_bib99","doi-asserted-by":"crossref","first-page":"1726","DOI":"10.1378\/chest.125.5.1726","article-title":"The effect of inhaled tiotropium bromide on lung mucociliary clearance in patients with COPD","volume":"125","author":"Hasani","year":"2004","journal-title":"Chest"},{"key":"2026032100521305400_bib100","doi-asserted-by":"crossref","first-page":"1592","DOI":"10.1164\/rccm.2105025","article-title":"The effects of inhaled fluticasone on airway inflammation in chronic obstructive pulmonary disease: a double-blind, placebo-controlled biopsy study","volume":"165","author":"Hattotuwa","year":"2002","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032100521305400_bib101","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1164\/rccm.200807-1056OC","article-title":"Ex vivo sputum analysis reveals impairment of protease-dependent mucus degradation by plasma proteins in acute asthma","volume":"180","author":"Innes","year":"2009","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032100521305400_bib102","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1016\/j.jaci.2005.01.036","article-title":"Effects of ciclesonide and fluticasone propionate on allergen-induced airway inflammation and remodeling features","volume":"115","author":"Leung","year":"2005","journal-title":"J Allergy Clin Immunol"},{"key":"2026032100521305400_bib103","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1165\/rcmb.2005-0176OC","article-title":"Dexamethasone-mediated repression of MUC5AC gene expression in human lung epithelial cells","volume":"34","author":"Chen","year":"2006","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026032100521305400_bib104","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1152\/jappl.1998.85.3.1086","article-title":"Budesonide affects allergic mucociliary dysfunction","volume":"85","author":"O\u2019Riordan","year":"1998","journal-title":"J Appl Physiol"},{"key":"2026032100521305400_bib105","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1136\/bmj.320.7245.1297","article-title":"Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial","volume":"320","author":"Burge","year":"2000","journal-title":"BMJ"},{"key":"2026032100521305400_bib106","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/S0140-6736(03)12459-2","article-title":"TRial of Inhaled STeroids ANd long-acting beta2 agonists study group. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial","volume":"361","author":"Calverley","year":"2003","journal-title":"Lancet"},{"key":"2026032100521305400_bib107","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1183\/09031936.03.00031402","article-title":"Efficacy and safety of budesonide\/formoterol in the management of chronic obstructive pulmonary disease","volume":"21","author":"Szafranski","year":"2003","journal-title":"Eur Respir J"},{"issue":"5","key":"2026032100521305400_bib108","first-page":"CD002309","article-title":"Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease","author":"Chong","year":"2011","journal-title":"Cochrane Database Syst Rev"},{"key":"2026032100521305400_bib109","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/S0140-6736(09)61255-1","article-title":"M2\u2013124 and M2\u2013125 study groups. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials","volume":"374","author":"Calverley","year":"2009","journal-title":"Lancet"},{"key":"2026032100521305400_bib110","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1016\/S0140-6736(09)61252-6","article-title":"M2\u2013127 and M2\u2013128 study groups. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials","volume":"374","author":"Fabbri","year":"2009","journal-title":"Lancet"},{"key":"2026032100521305400_bib111","doi-asserted-by":"crossref","first-page":"303S","DOI":"10.1378\/chest.117.5_suppl_1.303S-a","article-title":"Oxidants\/antioxidants and COPD","volume":"117","author":"MacNee","year":"2000","journal-title":"Chest"},{"key":"2026032100521305400_bib112","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.ejphar.2010.05.045","article-title":"Carbocisteine normalizes the viscous property of mucus through regulation of fucosylated and sialylated sugar chain on airway mucins","volume":"641","author":"Ishibashi","year":"2010","journal-title":"Eur J Pharmacol"},{"key":"2026032100521305400_bib113","doi-asserted-by":"crossref","first-page":"1552","DOI":"10.1016\/S0140-6736(05)66456-2","article-title":"Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trial","volume":"365","author":"Decramer","year":"2005","journal-title":"Lancet"},{"key":"2026032100521305400_bib114","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"},{"issue":"2","key":"2026032100521305400_bib115","first-page":"CD001287","article-title":"Mucolytic agents for chronic bronchitis or chronic obstructive pulmonary disease","author":"Poole","year":"2010","journal-title":"Cochrane Database Syst Rev"},{"key":"2026032100521305400_bib116","doi-asserted-by":"crossref","first-page":"52S","DOI":"10.1378\/chest.125.2_suppl.52S","article-title":"Macrolides for the treatment of chronic sinusitis, asthma, and COPD","volume":"125","author":"Gotfried","year":"2004","journal-title":"Chest"},{"key":"2026032100521305400_bib117","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1164\/rccm.200801-145OC","article-title":"Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations","volume":"178","author":"Seemungal","year":"2008","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032100521305400_bib118","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1056\/NEJMoa1104623","article-title":"Azithromycin for prevention of exacerbations of COPD","volume":"365","author":"Albert","year":"2011","journal-title":"N Engl J Med"},{"key":"2026032100521305400_bib119","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1016\/j.rmed.2011.02.003","article-title":"Cough and sputum production as risk factors for poor outcomes in patients with COPD","volume":"105","author":"Miravitlles","year":"2011","journal-title":"Respir Med"},{"key":"2026032100521305400_bib120","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1513\/pats.200802-014ET","article-title":"New concepts in the pathobiology of chronic obstructive pulmonary disease","volume":"5","author":"Kim","year":"2008","journal-title":"Proc Am Thor Soc"},{"key":"2026032100521305400_bib121","first-page":"688","article-title":"Is respiratory mucus hypersecretion really an innocent disorder? A 22-year mortality survey of 1,061 working men","volume":"134","author":"Annesi","year":"1986","journal-title":"Am Rev Respir Dis"},{"key":"2026032100521305400_bib122","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1183\/09031936.00022412","article-title":"Chronic cough and sputum production: a clinical COPD phenotype?","volume":"40","author":"Burgel","year":"2012","journal-title":"Eur Respir J"}],"container-title":["American Journal of Respiratory and Critical Care Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajrccm\/article-pdf\/187\/3\/228\/67269744\/ajrccm_187_3_228.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajrccm\/article-pdf\/187\/3\/228\/67269744\/ajrccm_187_3_228.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T04:53:24Z","timestamp":1774068804000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajrccm\/article\/187\/3\/228\/8509988"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,2,1]]},"references-count":122,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2013,2,1]]},"published-print":{"date-parts":[[2013,2,1]]}},"URL":"https:\/\/doi.org\/10.1164\/rccm.201210-1843ci","relation":{},"ISSN":["1073-449X","1535-4970"],"issn-type":[{"value":"1073-449X","type":"print"},{"value":"1535-4970","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2013,2]]},"published":{"date-parts":[[2013,2,1]]}}}