{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T07:17:12Z","timestamp":1789802232335,"version":"4.0.1"},"reference-count":44,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2015,12,1]],"date-time":"2015-12-01T00:00:00Z","timestamp":1448928000000},"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":[[2015,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, exists in several isoforms, which differentially impacts neuronal and immune cell survival and differentiation. The role of BDNF and its isoforms in asthma remains unclear. The objectives of this study were to compare the BDNF protein isoforms and specific splice variant expression in sputum and bronchoscopic samples from healthy control subjects and participants with asthma, and to relate these changes to findings in IL-13\u2013stimulated human airway epithelial cells. Sputum and bronchoscopic samples from healthy control subjects and participants with asthma were evaluated for BDNF protein (ELISA and Western blot) and BDNF mRNA (gel and quantitative real-time PCR) in relation to asthma severity and type 2 inflammatory processes. BDNF mRNA was measured in cultured primary human airway epithelial cells after IL-13 stimulation. Total BDNF protein differed among the groups, and its mature isoform was significantly higher in sputum from subjects with severe asthma compared with healthy control subjects (overall P\u2009=\u20090.008, P\u2009=\u20090.027, respectively). Total BDNF was higher in those with elevated fractional exhaled nitric oxide and sputum eosinophilia. In vitro, IL-13 increased BDNF exon VIb splice variant and the ratio to BDNF common exon IX mRNA (P\u2009&amp;lt;\u20090.001, P\u2009=\u20090.003, respectively). Epithelial brushing exon VIb mRNA and total BDNF protein differed among the groups and were higher in subjects with severe asthma than in healthy control subjects (overall P\u2009=\u20090.01, P\u2009=\u20090.02, respectively). The mature BDNF isoform and the exon VIb splice variant are increased in human asthmatic airways. The in vitro increase in response to IL-13 suggests that type 2 cytokines regulate BDNF levels and activity in asthma.<\/jats:p>","DOI":"10.1165\/rcmb.2015-0015oc","type":"journal-article","created":{"date-parts":[[2015,5,6]],"date-time":"2015-05-06T12:42:47Z","timestamp":1430916167000},"page":"844-852","source":"Crossref","is-referenced-by-count":54,"title":["Brain-Derived Neurotrophic Factor Expression in Asthma. Association with Severity and Type 2 Inflammatory Processes"],"prefix":"10.1093","volume":"53","author":[{"given":"Tetsuya","family":"Watanabe","sequence":"first","affiliation":[{"name":"Asthma Institute at University of Pittsburgh Medical Center, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9143-7712","authenticated-orcid":false,"given":"Merritt L.","family":"Fajt","sequence":"additional","affiliation":[{"name":"Asthma Institute at University of Pittsburgh Medical Center, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John B.","family":"Trudeau","sequence":"additional","affiliation":[{"name":"Asthma Institute at University of Pittsburgh Medical Center, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nipasiri","family":"Voraphani","sequence":"additional","affiliation":[{"name":"Asthma Institute at University of Pittsburgh Medical Center, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haizhen","family":"Hu","sequence":"additional","affiliation":[{"name":"Asthma Institute at University of Pittsburgh Medical Center, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuxia","family":"Zhou","sequence":"additional","affiliation":[{"name":"Asthma Institute at University of Pittsburgh Medical Center, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Holguin","sequence":"additional","affiliation":[{"name":"Asthma Institute at University of Pittsburgh Medical Center, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sally E.","family":"Wenzel","sequence":"additional","affiliation":[{"name":"Asthma Institute at University of Pittsburgh Medical Center, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2015,12,1]]},"reference":[{"key":"2026021122342288500_bib1","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1165\/rcmb.2002-0110OC","article-title":"Neurotrophin and neurotrophin receptor protein expression in the human lung","volume":"30","author":"Ricci","year":"2004","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026021122342288500_bib2","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1164\/rccm.200406-758OC","article-title":"Brain-derived neurotrophic factor in platelets and airflow limitation in asthma","volume":"171","author":"Lommatzsch","year":"2005","journal-title":"Am J Respir Crit Care Med"},{"key":"2026021122342288500_bib3","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1093\/cvr\/cvr107","article-title":"Neurotrophins induce nitric oxide generation in human pulmonary artery endothelial cells","volume":"91","author":"Meuchel","year":"2011","journal-title":"Cardiovasc Res"},{"key":"2026021122342288500_bib4","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1186\/1465-9921-13-116","article-title":"Stage-dependent association of BDNF and TGF-\u03b21 with lung function in stable COPD","volume":"13","author":"Stoll","year":"2012","journal-title":"Respir Res"},{"key":"2026021122342288500_bib5","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1165\/rcmb.2012-0129OC","article-title":"Brain-derived neurotrophic factor in cigarette smoke\u2013induced airway hyperreactivity","volume":"48","author":"Sathish","year":"2013","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026021122342288500_bib6","doi-asserted-by":"crossref","first-page":"e247","DOI":"10.1111\/apa.12224","article-title":"Association between brain-derived neurothropic factor variants and asthma in Chinese Han children","volume":"102","author":"Yinli","year":"2013","journal-title":"Acta Paediatr"},{"key":"2026021122342288500_bib7","doi-asserted-by":"crossref","first-page":"2002","DOI":"10.1164\/ajrccm.158.6.9803023","article-title":"Neurotrophins are increased in bronchoalveolar lavage fluid after segmental allergen provocation","volume":"158","author":"Virchow","year":"1998","journal-title":"Am J Respir Crit Care Med"},{"key":"2026021122342288500_bib8","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1016\/j.jaci.2010.02.008","article-title":"Analyses of asthma severity phenotypes and inflammatory proteins in subjects stratified by sputum granulocytes","volume":"125","author":"Hastie","year":"2010","journal-title":"J Allergy Clin Immunol"},{"key":"2026021122342288500_bib9","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/j.ygeno.2007.05.004","article-title":"Dissecting the human BDNF locus: bidirectional transcription, complex splicing, and multiple promoters","volume":"90","author":"Pruunsild","year":"2007","journal-title":"Genomics"},{"key":"2026021122342288500_bib10","doi-asserted-by":"crossref","first-page":"16813","DOI":"10.1073\/pnas.1014168108","article-title":"Spatial segregation of BDNF transcripts enables BDNF to differentially shape distinct dendritic compartments","volume":"108","author":"Baj","year":"2011","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026021122342288500_bib11","doi-asserted-by":"crossref","first-page":"1945","DOI":"10.1126\/science.1065057","article-title":"Regulation of cell survival by secreted proneurotrophins","volume":"294","author":"Lee","year":"2001","journal-title":"Science"},{"key":"2026021122342288500_bib12","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1038\/nn1510","article-title":"Activation of p75NTR by proBDNF facilitates hippocampal long-term depression","volume":"8","author":"Woo","year":"2005","journal-title":"Nat Neurosci"},{"key":"2026021122342288500_bib13","doi-asserted-by":"crossref","first-page":"12660","DOI":"10.1074\/jbc.M008104200","article-title":"Biosynthesis and post-translational processing of the precursor to brain-derived neurotrophic factor","volume":"276","author":"Mowla","year":"2001","journal-title":"J Biol Chem"},{"key":"2026021122342288500_bib14","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1126\/science.1100135","article-title":"Cleavage of proBDNF by tPA\/plasmin is essential for long-term hippocampal plasticity","volume":"306","author":"Pang","year":"2004","journal-title":"Science"},{"key":"2026021122342288500_bib15","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1016\/j.archoralbio.2009.04.005","article-title":"Identification of pro- and mature brain-derived neurotrophic factor in human saliva","volume":"54","author":"Mandel","year":"2009","journal-title":"Arch Oral Biol"},{"key":"2026021122342288500_bib16","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1073\/pnas.96.4.1321","article-title":"Mammalian subtilisin\/kexin isozyme SKI-1: a widely expressed proprotein convertase with a unique cleavage specificity and cellular localization","volume":"96","author":"Seidah","year":"1999","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026021122342288500_bib17","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1016\/j.jaci.2005.12.1339","article-title":"Airway epithelial cells produce neurotrophins and promote the survival of eosinophils during allergic airway inflammation","volume":"117","author":"Hahn","year":"2006","journal-title":"J Allergy Clin Immunol"},{"key":"2026021122342288500_bib18","first-page":"225","article-title":"Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, November 1986","volume":"136","year":"1987","journal-title":"Am Rev Respir Dis"},{"key":"2026021122342288500_bib19","doi-asserted-by":"crossref","first-page":"2341","DOI":"10.1164\/ajrccm.162.6.ats9-00","article-title":"Proceedings of the ATS workshop on refractory asthma: current understanding, recommendations, and unanswered questions","volume":"162","author":"American Thoracic Society","year":"2000","journal-title":"Am J Respir Crit Care Med"},{"key":"2026021122342288500_bib20","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/j.jaci.2006.11.639","article-title":"Characterization of the severe asthma phenotype by the National Heart, Lung, and Blood Institute\u2019s Severe Asthma Research Program","volume":"119","author":"Moore","year":"2007","journal-title":"J Allergy Clin Immunol"},{"key":"2026021122342288500_bib21","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1164\/ajrccm\/147.5.1126","article-title":"Cellular and biochemical analysis of induced sputum from asthmatic and from healthy subjects","volume":"147","author":"Fahy","year":"1993","journal-title":"Am Rev Respir Dis"},{"key":"2026021122342288500_bib22","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1111\/j.1365-2222.2008.02969.x","article-title":"IL-13 induced increases in nitrite levels are primarily driven by increases in inducible nitric oxide synthase as compared with effects on arginases in human primary bronchial epithelial cells","volume":"38","author":"Chibana","year":"2008","journal-title":"Clin Exp Allergy"},{"key":"2026021122342288500_bib23","doi-asserted-by":"crossref","first-page":"1446","DOI":"10.1016\/j.jaci.2006.01.049","article-title":"Selective downregulation of prostaglandin E2-related pathways by the Th2 cytokine IL-13","volume":"117","author":"Trudeau","year":"2006","journal-title":"J Allergy Clin Immunol"},{"key":"2026021122342288500_bib24","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1164\/rccm.200811-1744OC","article-title":"Interleukin-13\u2013induced MUC5AC is regulated by 15-lipoxygenase 1 pathway in human bronchial epithelial cells","volume":"179","author":"Zhao","year":"2009","journal-title":"Am J Respir Crit Care Med"},{"key":"2026021122342288500_bib25","doi-asserted-by":"crossref","first-page":"2455","DOI":"10.1056\/NEJMoa1304048","article-title":"Dupilumab in persistent asthma with elevated eosinophil levels","volume":"368","author":"Wenzel","year":"2013","journal-title":"N Engl J Med"},{"key":"2026021122342288500_bib26","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1164\/rccm.201109-1640OC","article-title":"A large subgroup of mild-to-moderate asthma is persistently noneosinophilic","volume":"185","author":"McGrath","year":"2012","journal-title":"Am J Respir Crit Care Med"},{"key":"2026021122342288500_bib27","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1038\/nbt.2158","article-title":"Inhibition of natural antisense transcripts in vivo results in gene-specific transcriptional upregulation","volume":"30","author":"Modarresi","year":"2012","journal-title":"Nat Biotechnol"},{"key":"2026021122342288500_bib28","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1097\/NEN.0b013e31824b27e4","article-title":"Altered balance of proteolytic isoforms of pro\u2013brain-derived neurotrophic factor in autism","volume":"71","author":"Garcia","year":"2012","journal-title":"J Neuropathol Exp Neurol"},{"key":"2026021122342288500_bib29","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1016\/j.jaci.2012.06.025","article-title":"Periostin is a systemic biomarker of eosinophilic airway inflammation in asthmatic patients","volume":"130","author":"Jia","year":"2012","journal-title":"J Allergy Clin Immunol"},{"key":"2026021122342288500_bib30","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1164\/rccm.201406-1099OC","article-title":"Gene expression in relation to exhaled nitric oxide identifies novel asthma phenotypes with unique biomolecular pathways","volume":"190","author":"Modena","year":"2014","journal-title":"Am J Respir Crit Care Med"},{"key":"2026021122342288500_bib31","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1136\/thx.2008.110916","article-title":"Adverse effects of salmeterol in asthma: a neuronal perspective","volume":"64","author":"Lommatzsch","year":"2009","journal-title":"Thorax"},{"key":"2026021122342288500_bib32","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1038\/ni.1719","article-title":"Divergent functions for airway epithelial matrix metalloproteinase 7 and retinoic acid in experimental asthma","volume":"10","author":"Goswami","year":"2009","journal-title":"Nat Immunol"},{"key":"2026021122342288500_bib33","first-page":"518","article-title":"Concentrations of plasminogen activator inhibitor-1 (PAI-1) and urokinase plasminogen activator (uPA) in induced sputum of asthma patients after allergen challenge","volume":"48","author":"Kowal","year":"2010","journal-title":"Folia Histochem Cytobiol"},{"key":"2026021122342288500_bib34","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1038\/nn.2244","article-title":"Neuronal release of proBDNF","volume":"12","author":"Yang","year":"2009","journal-title":"Nat Neurosci"},{"key":"2026021122342288500_bib35","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1084\/jem.189.5.865","article-title":"Activated human T cells, B cells, and monocytes produce brain-derived neurotrophic factor in vitro and in inflammatory brain lesions: a neuroprotective role of inflammation?","volume":"189","author":"Kerschensteiner","year":"1999","journal-title":"J Exp Med"},{"key":"2026021122342288500_bib36","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.jneuroim.2005.01.023","article-title":"A role for brain-derived neurotrophic factor in B cell development","volume":"163","author":"Schuhmann","year":"2005","journal-title":"J Neuroimmunol"},{"key":"2026021122342288500_bib37","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.jns.2012.07.016","article-title":"Altered serum content of brain-derived neurotrophic factor isoforms in multiple sclerosis","volume":"320","author":"Tongiorgi","year":"2012","journal-title":"J Neurol Sci"},{"key":"2026021122342288500_bib38","doi-asserted-by":"crossref","first-page":"1268","DOI":"10.1016\/j.jaci.2005.02.007","article-title":"Brain-derived neurotrophic factor is increased in atopic dermatitis and modulates eosinophil functions compared with that seen in nonatopic subjects","volume":"115","author":"Raap","year":"2005","journal-title":"J Allergy Clin Immunol"},{"key":"2026021122342288500_bib39","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1084\/jem.20010897","article-title":"The neurotrophins nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4 are survival and activation factors for eosinophils in patients with allergic bronchial asthma","volume":"198","author":"Nassenstein","year":"2003","journal-title":"J Exp Med"},{"key":"2026021122342288500_bib40","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/j.jaci.2006.04.052","article-title":"Pulmonary distribution, regulation, and functional role of Trk receptors in a murine model of asthma","volume":"118","author":"Nassenstein","year":"2006","journal-title":"J Allergy Clin Immunol"},{"key":"2026021122342288500_bib41","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1038\/sj.bjp.0705638","article-title":"Brain-derived neurotrophic factor (BDNF) contributes to neuronal dysfunction in a model of allergic airway inflammation","volume":"141","author":"Braun","year":"2004","journal-title":"Br J Pharmacol"},{"key":"2026021122342288500_bib42","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1038\/337362a0","article-title":"Nerve growth factor regulates expression of neuropeptide genes in adult sensory neurons","volume":"337","author":"Lindsay","year":"1989","journal-title":"Nature"},{"key":"2026021122342288500_bib43","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.tig.2006.01.001","article-title":"Regulation of gene expression by alternative untranslated regions","volume":"22","author":"Hughes","year":"2006","journal-title":"Trends Genet"},{"key":"2026021122342288500_bib44","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/S0378-1119(01)00674-6","article-title":"Structural and functional features of eukaryotic mRNA untranslated regions","volume":"276","author":"Pesole","year":"2001","journal-title":"Gene"}],"container-title":["American Journal of Respiratory Cell and Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article-pdf\/53\/6\/844\/66810154\/ajrcmb_53_6_844.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article-pdf\/53\/6\/844\/66810154\/ajrcmb_53_6_844.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T03:36:35Z","timestamp":1770867395000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article\/53\/6\/844\/8467889"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,12,1]]},"references-count":44,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2015,12,1]]},"published-print":{"date-parts":[[2015,12,1]]}},"URL":"https:\/\/doi.org\/10.1165\/rcmb.2015-0015oc","relation":{},"ISSN":["1044-1549","1535-4989"],"issn-type":[{"value":"1044-1549","type":"print"},{"value":"1535-4989","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2015,12]]},"published":{"date-parts":[[2015,12,1]]}}}