{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T09:16:41Z","timestamp":1792660601187,"version":"4.5.0"},"reference-count":52,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2014,1,1]],"date-time":"2014-01-01T00:00:00Z","timestamp":1388534400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Oxidative stress has been implicated in the pathogenesis of bronchial asthma. Besides granulocytes, the airway epithelium can produce large amounts of reactive oxygen species and can contribute to asthma-related oxidative stress. Histamine is a major inflammatory mediator present in large quantities in asthmatic airways. Whether histamine triggers epithelium-derived oxidative stress is unknown. We therefore aimed at characterizing human airway epithelial H2O2 production stimulated by histamine. We found that air\u2013liquid interface cultures of primary human bronchial epithelial cells (BECs) and an immortalized BEC model (Cdk4\/hTERT HBEC) produce H2O2 in response to histamine. The main source of airway epithelial H2O2 is an NADPH dual oxidase, Duox1. Out of the four histamine receptors (H1R\u2013H4R), H1R has the highest expression in BECs and mediates the H2O2\u2013producing effects of histamine. IL-4 induces Duox1 gene and protein expression levels and enhances histamine-induced H2O2 production by epithelial cells. Using HEK-293 cells expressing Duox1 or Duox2 and endogenous H1R, histamine triggers an immediate intracellular calcium signal and H2O2 release. Overexpression of H1R further increases the oxidative output of Duox-expressing HEK-293 cells. Our observations show that BECs respond to histamine with Duox-mediated H2O2 production. These findings reveal a mechanism that could be an important contributor to oxidative stress characteristic of asthmatic airways, suggesting novel therapeutic targets for treating asthmatic airway disease.<\/jats:p>","DOI":"10.1165\/rcmb.2013-0254oc","type":"journal-article","created":{"date-parts":[[2013,8,20]],"date-time":"2013-08-20T11:57:20Z","timestamp":1376999840000},"page":"125-134","source":"Crossref","is-referenced-by-count":38,"title":["Histamine Stimulates Hydrogen Peroxide Production by Bronchial Epithelial Cells via Histamine H1 Receptor and Dual Oxidase"],"prefix":"10.1093","volume":"50","author":[{"given":"Bal\u00e1zs","family":"Rada","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, Georgia; and"},{"name":"Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Howard E.","family":"Boudreau","sequence":"additional","affiliation":[{"name":"Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan J.","family":"Park","sequence":"additional","affiliation":[{"name":"Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas L.","family":"Leto","sequence":"additional","affiliation":[{"name":"Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2014,1,1]]},"reference":[{"key":"2026030623204478600_bib1","first-page":"S41","article-title":"Function of the airway epithelium in asthma","volume":"26","author":"Leonardi","year":"2012","journal-title":"J Biol Regul Homeost Agents"},{"key":"2026030623204478600_bib2","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1164\/ajrccm.149.2.8306055","article-title":"Oxidative epithelial damage produces hyperresponsiveness of human peripheral airways","volume":"149","author":"Hulsmann","year":"1994","journal-title":"Am J Respir Crit Care Med"},{"key":"2026030623204478600_bib3","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1378\/chest.120.4.1136","article-title":"Elevated concentrations of exhaled hydrogen peroxide in asthmatic patients","volume":"120","author":"Emelyanov","year":"2001","journal-title":"Chest"},{"key":"2026030623204478600_bib4","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1378\/chest.121.2.338","article-title":"The relationships among hydrogen peroxide in expired breath condensate, airway inflammation, and asthma severity","volume":"121","author":"Loukides","year":"2002","journal-title":"Chest"},{"key":"2026030623204478600_bib5","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1183\/09031936.97.10030519","article-title":"Hydrogen peroxide in exhaled air is increased in stable asthmatic children","volume":"10","author":"Jobsis","year":"1997","journal-title":"Eur Respir J"},{"key":"2026030623204478600_bib6","doi-asserted-by":"crossref","first-page":"1042","DOI":"10.1164\/ajrccm.158.4.9710091","article-title":"Combined use of exhaled hydrogen peroxide and nitric oxide in monitoring asthma","volume":"158","author":"Horvath","year":"1998","journal-title":"Am J Respir Crit Care Med"},{"key":"2026030623204478600_bib7","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.coph.2004.01.011","article-title":"Airway mucus hypersecretion in asthma: an undervalued pathology?","volume":"4","author":"Rogers","year":"2004","journal-title":"Curr Opin Pharmacol"},{"key":"2026030623204478600_bib8","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1002\/(SICI)1099-0496(1999)27:18+<54::AID-PPUL17>3.0.CO;2-R","article-title":"Mechanisms of hypersecretion in acute asthma, proposed cause of death, and novel therapy","volume":"18","author":"Nadel","year":"1999","journal-title":"Pediatr Pulmonol Suppl"},{"key":"2026030623204478600_bib9","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.4049\/jimmunol.164.3.1546","article-title":"Oxidative stress causes mucin synthesis via transactivation of epidermal growth factor receptor: role of neutrophils","volume":"164","author":"Takeyama","year":"2000","journal-title":"J Immunol"},{"key":"2026030623204478600_bib10","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1093\/toxsci\/67.2.275","article-title":"Silica-induced generation of extracellular factor(s) increases reactive oxygen species in human bronchial epithelial cells","volume":"67","author":"Deshpande","year":"2002","journal-title":"Toxicol Sci"},{"key":"2026030623204478600_bib11","doi-asserted-by":"crossref","first-page":"23227","DOI":"10.1074\/jbc.M000916200","article-title":"Cloning of two human thyroid cDNAs encoding new members of the NADPH oxidase family","volume":"275","author":"De Deken","year":"2000","journal-title":"J Biol Chem"},{"key":"2026030623204478600_bib12","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1038\/mi.2010.62","article-title":"Reactive oxygen species mediate inflammatory cytokine release and EGFR-dependent mucin secretion in airway epithelial cells exposed to Pseudomonas pyocyanin","volume":"4","author":"Rada","year":"2011","journal-title":"Mucosal Immunol"},{"key":"2026030623204478600_bib13","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1016\/j.febslet.2010.01.025","article-title":"Characterization of hydrogen peroxide production by Duox in bronchial epithelial cells exposed to Pseudomonas aeruginosa","volume":"584","author":"Rada","year":"2010","journal-title":"FEBS Lett"},{"key":"2026030623204478600_bib14","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.tim.2012.10.004","article-title":"Pyocyanin effects on respiratory epithelium: relevance in Pseudomonas aeruginosa airway infections","volume":"21","author":"Rada","year":"2013","journal-title":"Trends Microbiol"},{"key":"2026030623204478600_bib15","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1016\/j.bbagen.2011.03.004","article-title":"Nox enzymes in allergic airway inflammation","volume":"1810","author":"van der Vliet","year":"2011","journal-title":"Biochim Biophys Acta"},{"key":"2026030623204478600_bib16","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1164\/rccm.201204-0786OC","article-title":"Asthmatic airway neutrophilia after allergen challenge is associated with the glutathione S-transferase M1 genotype","volume":"187","author":"Hoskins","year":"2013","journal-title":"Am J Respir Crit Care Med"},{"key":"2026030623204478600_bib17","doi-asserted-by":"crossref","first-page":"5948","DOI":"10.4049\/jimmunol.167.10.5948","article-title":"Human eosinophils induce mucin production in airway epithelial cells via epidermal growth factor receptor activation","volume":"167","author":"Burgel","year":"2001","journal-title":"J Immunol"},{"key":"2026030623204478600_bib18","doi-asserted-by":"crossref","first-page":"4883","DOI":"10.4049\/jimmunol.181.7.4883","article-title":"The Pseudomonas toxin pyocyanin inhibits the dual oxidase-based antimicrobial system as it imposes oxidative stress on airway epithelial cells","volume":"181","author":"Rada","year":"2008","journal-title":"J Immunol"},{"key":"2026030623204478600_bib19","doi-asserted-by":"crossref","first-page":"1502","DOI":"10.1096\/fj.02-1104fje","article-title":"Dual oxidases represent novel hydrogen peroxide sources supporting mucosal surface host defense","volume":"17","author":"Geiszt","year":"2003","journal-title":"FASEB J"},{"key":"2026030623204478600_bib20","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1165\/rcmb.2004-0302OC","article-title":"Regulated hydrogen peroxide production by Duox in human airway epithelial cells","volume":"32","author":"Forteza","year":"2005","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026030623204478600_bib21","doi-asserted-by":"crossref","first-page":"37265","DOI":"10.1074\/jbc.274.52.37265","article-title":"Purification of a novel flavoprotein involved in the thyroid NADPH oxidase: cloning of the porcine and human cdnas","volume":"274","author":"Dupuy","year":"1999","journal-title":"J Biol Chem"},{"key":"2026030623204478600_bib22","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1096\/fj.08-120006","article-title":"Duox maturation factors form cell surface complexes with Duox affecting the specificity of reactive oxygen species generation","volume":"23","author":"Morand","year":"2009","journal-title":"FASEB J"},{"key":"2026030623204478600_bib23","doi-asserted-by":"crossref","first-page":"30046","DOI":"10.1074\/jbc.M500516200","article-title":"Dual oxidase-2 has an intrinsic Ca2+-dependent H2O2-generating activity","volume":"280","author":"Ameziane-El-Hassani","year":"2005","journal-title":"J Biol Chem"},{"key":"2026030623204478600_bib24","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1073\/pnas.0408932102","article-title":"Dual oxidase 1-dependent MUC5AC mucin expression in cultured human airway epithelial cells","volume":"102","author":"Shao","year":"2005","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026030623204478600_bib25","doi-asserted-by":"crossref","first-page":"3213","DOI":"10.1074\/jbc.M606533200","article-title":"Airway epithelial cell migration and wound repair by ATP-mediated activation of dual oxidase 1","volume":"282","author":"Wesley","year":"2007","journal-title":"J Biol Chem"},{"key":"2026030623204478600_bib26","doi-asserted-by":"crossref","first-page":"36454","DOI":"10.1074\/jbc.M404983200","article-title":"NADPH oxidase-dependent acid production in airway epithelial cells","volume":"279","author":"Schwarzer","year":"2004","journal-title":"J Biol Chem"},{"key":"2026030623204478600_bib27","doi-asserted-by":"crossref","first-page":"17858","DOI":"10.1074\/jbc.M809761200","article-title":"ATP-mediated activation of the NADPH oxidase DUOX1 mediates airway epithelial responses to bacterial stimuli","volume":"284","author":"Boots","year":"2009","journal-title":"J Biol Chem"},{"key":"2026030623204478600_bib28","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1164\/rccm.200607-1029OC","article-title":"A novel host defense system of airways is defective in cystic fibrosis","volume":"175","author":"Moskwa","year":"2007","journal-title":"Am J Respir Crit Care Med"},{"key":"2026030623204478600_bib29","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1165\/ajrcmb.22.6.3980","article-title":"The lactoperoxidase system functions in bacterial clearance of airways","volume":"22","author":"Gerson","year":"2000","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026030623204478600_bib30","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.freeradbiomed.2013.06.012","article-title":"Dual oxidase regulates neutrophil recruitment in allergic airways","volume":"65C","author":"Chang","year":"2013","journal-title":"Free Radic Biol Med"},{"key":"2026030623204478600_bib31","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1165\/rcmb.2012-0393OC","article-title":"Dual oxidase-1 is required for airway epithelial cell migration and bronchiolar reepithelialization after injury","volume":"48","author":"Gorissen","year":"2013","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026030623204478600_bib32","doi-asserted-by":"crossref","first-page":"1786","DOI":"10.1111\/j.1365-2222.2009.03374.x","article-title":"Histamine, histamine receptors and their role in immune pathology","volume":"39","author":"Jutel","year":"2009","journal-title":"Clin Exp Allergy"},{"key":"2026030623204478600_bib33","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1016\/j.jaci.2011.06.051","article-title":"Regulation of the immune response and inflammation by histamine and histamine receptors","volume":"128","author":"O'Mahony","year":"2011","journal-title":"J Allergy Clin Immunol"},{"key":"2026030623204478600_bib34","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1016\/j.bcp.2004.10.006","article-title":"Histamine H1 receptor antagonist blocks histamine-induced proinflammatory cytokine production through inhibition of Ca2+-dependent protein kinase C, Raf\/MEK\/ERK and IKK\/I kappa B\/NF-kappa B signal cascades","volume":"69","author":"Matsubara","year":"2005","journal-title":"Biochem Pharmacol"},{"key":"2026030623204478600_bib35","doi-asserted-by":"crossref","first-page":"1704","DOI":"10.1096\/fj.11-197061","article-title":"Histamine may induce airway remodeling through release of epidermal growth factor receptor ligands from bronchial epithelial cells","volume":"26","author":"Hirota","year":"2012","journal-title":"FASEB J"},{"key":"2026030623204478600_bib36","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1159\/000104419","article-title":"Histamine induces MUC5AC expression via a hCLCA1 pathway","volume":"80","author":"Kim","year":"2007","journal-title":"Pharmacology"},{"key":"2026030623204478600_bib37","doi-asserted-by":"crossref","first-page":"S37","DOI":"10.3109\/00016489.2012.661075","article-title":"Histamine regulates mucin expression through H1 receptor in airway epithelial cells","volume":"132","author":"Kim","year":"2012","journal-title":"Acta Otolaryngol"},{"key":"2026030623204478600_bib38","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1165\/ajrcmb.14.1.8534481","article-title":"Mucociliary differentiation of serially passaged normal human tracheobronchial epithelial cells","volume":"14","author":"Gray","year":"1996","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026030623204478600_bib39","doi-asserted-by":"crossref","first-page":"9027","DOI":"10.1158\/0008-5472.CAN-04-3703","article-title":"Immortalization of human bronchial epithelial cells in the absence of viral oncoproteins","volume":"64","author":"Ramirez","year":"2004","journal-title":"Cancer Res"},{"key":"2026030623204478600_bib40","first-page":"141","article-title":"A three-dimensional model of differentiation of immortalized human bronchial epithelial cells","volume-title":"Differentiation","author":"Vaughan","year":"2006"},{"key":"2026030623204478600_bib41","doi-asserted-by":"crossref","first-page":"5951","DOI":"10.1073\/pnas.85.16.5951","article-title":"Characterization of human tracheal epithelial cells transformed by an origin-defective simian virus 40","volume":"85","author":"Gruenert","year":"1988","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026030623204478600_bib42","doi-asserted-by":"crossref","first-page":"5144","DOI":"10.4049\/jimmunol.178.8.5144","article-title":"Thiocyanate transport in resting and IL-4-stimulated human bronchial epithelial cells: role of pendrin and anion channels","volume":"178","author":"Pedemonte","year":"2007","journal-title":"J Immunol"},{"key":"2026030623204478600_bib43","first-page":"925","article-title":"Functional characterization of histamine receptor subtypes in a human bronchial epithelial cell line","volume":"18","author":"Muller","year":"2006","journal-title":"Int J Mol Med"},{"key":"2026030623204478600_bib44","doi-asserted-by":"crossref","first-page":"4911","DOI":"10.1016\/j.febslet.2005.08.002","article-title":"Differential regulation of dual NADPH oxidases\/peroxidases, Duox1 and Duox2, by Th1 and Th2 cytokines in respiratory tract epithelium","volume":"579","author":"Harper","year":"2005","journal-title":"FEBS Lett"},{"key":"2026030623204478600_bib45","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/S0091-6749(86)80083-5","article-title":"The role of hydrogen peroxide in basophil histamine release and the effect of selected flavonoids","volume":"78","author":"Ogasawara","year":"1986","journal-title":"J Allergy Clin Immunol"},{"key":"2026030623204478600_bib46","first-page":"174","article-title":"Histamine release during intestinal ischemia-reperfusion: role of iron ions and hydrogen peroxide","volume":"35","author":"Boros","year":"1991","journal-title":"Circ Shock"},{"key":"2026030623204478600_bib47","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1158\/0008-5472.CAN-07-5782","article-title":"Silencing of DUOX NADPH oxidases by promoter hypermethylation in lung cancer","volume":"68","author":"Luxen","year":"2008","journal-title":"Cancer Res"},{"key":"2026030623204478600_bib48","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1124\/mol.60.5.1133","article-title":"Histamine H(1)-receptor activation of nuclear factor-kappa B: roles for G beta gamma- and G alpha(q\/11)-subunits in constitutive and agonist-mediated signaling","volume":"60","author":"Bakker","year":"2001","journal-title":"Mol Pharmacol"},{"key":"2026030623204478600_bib49","doi-asserted-by":"crossref","first-page":"1624","DOI":"10.1172\/JCI26150","article-title":"The H1 histamine receptor regulates allergic lung responses","volume":"116","author":"Bryce","year":"2006","journal-title":"J Clin Invest"},{"key":"2026030623204478600_bib50","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1016\/j.jaci.2012.06.034","article-title":"IL-13 in asthma and allergic disease: asthma phenotypes and targeted therapies","volume":"130","author":"Ingram","year":"2012","journal-title":"J Allergy Clin Immunol"},{"key":"2026030623204478600_bib51","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1165\/rcmb.2012-0080TR","article-title":"Targeting interleukin-4 in asthma: lost in translation?","volume":"47","author":"Maes","year":"2012","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026030623204478600_bib52","doi-asserted-by":"crossref","first-page":"1432","DOI":"10.2174\/092986711795328418","article-title":"Exhaled breath condensate in asthma: from bench to bedside","volume":"18","author":"Loukides","year":"2011","journal-title":"Curr Med Chem"}],"container-title":["American Journal of Respiratory Cell and Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article-pdf\/50\/1\/125\/67116793\/ajrcmb_50_1_125.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article-pdf\/50\/1\/125\/67116793\/ajrcmb_50_1_125.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,7]],"date-time":"2026-03-07T04:21:07Z","timestamp":1772857267000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article\/50\/1\/125\/8492675"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,1,1]]},"references-count":52,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2014,1,1]]},"published-print":{"date-parts":[[2014,1,1]]}},"URL":"https:\/\/doi.org\/10.1165\/rcmb.2013-0254oc","relation":{},"ISSN":["1044-1549","1535-4989"],"issn-type":[{"value":"1044-1549","type":"print"},{"value":"1535-4989","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2014,1]]},"published":{"date-parts":[[2014,1,1]]}}}