{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T18:22:18Z","timestamp":1792002138196,"version":"4.4.0"},"reference-count":38,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2019,6,1]],"date-time":"2019-06-01T00:00:00Z","timestamp":1559347200000},"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":[[2019,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Mucus overproduction is a major contributor to morbidity and mortality in asthma. Mucus overproduction is induced by orchestrated actions of multiple factors that include inflammatory cytokines and \u03b3-aminobutyric acid (GABA). GABA is produced only by pulmonary neuroendocrine cells (PNECs) in the mouse lung. Recent studies in a neonatal mouse model of allergic inflammation have shown that PNECs play an essential role in mucus overproduction by GABA hypersecretion. Whether PNECs mediate dysregulated GABA signaling for mucus overproduction in asthma is unknown. In this study, we characterized the cellular source of GABA in the lungs of nonhuman primates and humans and assessed GABA secretion and signaling in primate disease models. We found that like in mice, PNECs were the major source of GABA in primate lungs. In addition, an infant nonhuman primate model of asthma exhibited an increase in GABA secretion. Furthermore, subjects with asthma had elevated levels of expression of a subset of GABA type \u03b1 (GABA\u03b1) and type \u03b2 (GABA\u03b2) receptors in airway epithelium compared with those of healthy control subjects. Last, employing a normal human bronchial epithelial cell model of preinduced mucus overproduction, we showed pharmaceutical blockade of GABA\u03b1 and GABA\u03b2 receptor signaling reversed the effect of IL-13 on MUC5AC gene expression and goblet cell proliferation. Together, our data demonstrate an evolutionarily conserved intraepithelial GABA signaling that, in concert with IL-13, plays an essential role in mucus overproduction. Our findings may offer new strategies to ameliorate mucus overproduction in patients with asthma by targeting PNEC secretion and GABA signaling.<\/jats:p>","DOI":"10.1165\/rcmb.2018-0179oc","type":"journal-article","created":{"date-parts":[[2018,12,20]],"date-time":"2018-12-20T14:47:50Z","timestamp":1545317270000},"page":"687-694","source":"Crossref","is-referenced-by-count":63,"title":["Pulmonary Neuroendocrine Cells Secrete \u03b3-Aminobutyric Acid to Induce Goblet Cell Hyperplasia in Primate Models"],"prefix":"10.1093","volume":"60","author":[{"given":"Juliana","family":"Barrios","sequence":"first","affiliation":[{"name":"The Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alvin T.","family":"Kho","sequence":"additional","affiliation":[{"name":"The Channing Division of Network Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linh","family":"Aven","sequence":"additional","affiliation":[{"name":"The Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer A.","family":"Mitchel","sequence":"additional","affiliation":[{"name":"Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-Ah","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott H.","family":"Randell","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa A.","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine, University of California, Davis, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelan G.","family":"Tantisira","sequence":"additional","affiliation":[{"name":"The Channing Division of Network Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2178-0080","authenticated-orcid":false,"given":"Xingbin","family":"Ai","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Brigham and Women\u2019s Hospital, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,6,1]]},"reference":[{"key":"2026012222062070900_bib1","doi-asserted-by":"crossref","first-page":"2233","DOI":"10.1056\/NEJMra0910061","article-title":"Airway mucus function and dysfunction","volume":"363","author":"Fahy","year":"2010","journal-title":"N Engl J Med"},{"key":"2026012222062070900_bib2","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1146\/annurev.med.53.082901.103921","article-title":"The pathophysiology of asthma","volume":"53","author":"Maddox","year":"2002","journal-title":"Annu Rev Med"},{"key":"2026012222062070900_bib3","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1016\/S0140-6736(08)61447-6","article-title":"Wheezing and bronchial hyper-responsiveness in early childhood as predictors of newly diagnosed asthma in early adulthood: a longitudinal birth-cohort study","volume":"372","author":"Stern","year":"2008","journal-title":"Lancet"},{"key":"2026012222062070900_bib4","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1096\/fj.13-238212","article-title":"An NT4\/TrkB-dependent increase in innervation links early-life allergen exposure to persistent airway hyperreactivity","volume":"28","author":"Aven","year":"2014","journal-title":"FASEB J"},{"key":"2026012222062070900_bib5","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.taap.2014.12.006","article-title":"Early life exposure to allergen and ozone results in altered development in adolescent rhesus macaque lungs","volume":"283","author":"Herring","year":"2015","journal-title":"Toxicol Appl Pharmacol"},{"key":"2026012222062070900_bib6","doi-asserted-by":"crossref","first-page":"1434","DOI":"10.1289\/ehp.0800511","article-title":"Prenatal and early, but not late, postnatal exposure of mice to sidestream tobacco smoke increases airway hyperresponsiveness later in life","volume":"117","author":"Wu","year":"2009","journal-title":"Environ Health Perspect"},{"key":"2026012222062070900_bib7","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.taap.2003.09.025","article-title":"Postnatal remodeling of the neural components of the epithelial-mesenchymal trophic unit in the proximal airways of infant rhesus monkeys exposed to ozone and allergen","volume":"194","author":"Larson","year":"2004","journal-title":"Toxicol Appl Pharmacol"},{"key":"2026012222062070900_bib8","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1016\/j.jaci.2008.04.038","article-title":"Perinatal environmental tobacco smoke exposure alters the immune response and airway innervation in infant primates","volume":"122","author":"Yu","year":"2008","journal-title":"J Allergy Clin Immunol"},{"key":"2026012222062070900_bib9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.resp.2015.11.009","article-title":"Side-stream tobacco smoke-induced airway hyperresponsiveness in early postnatal period is involved nerve growth factor","volume":"223","author":"Wu","year":"2016","journal-title":"Respir Physiol Neurobiol"},{"key":"2026012222062070900_bib10","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1007\/s11882-018-0765-y","article-title":"Neurotrophins in asthma","volume":"18","author":"Barrios","year":"2018","journal-title":"Curr Allergy Asthma Rep"},{"key":"2026012222062070900_bib11","doi-asserted-by":"crossref","first-page":"4335","DOI":"10.1096\/fj.201700186R","article-title":"Targeting acetylcholine receptor M3 prevents the progression of airway hyperreactivity in a mouse model of childhood asthma","volume":"31","author":"Patel","year":"2017","journal-title":"FASEB J"},{"key":"2026012222062070900_bib12","doi-asserted-by":"crossref","first-page":"4117","DOI":"10.1096\/fj.201700115R","article-title":"Early life allergen-induced mucus overproduction requires augmented neural stimulation of pulmonary neuroendocrine cell secretion","volume":"31","author":"Barrios","year":"2017","journal-title":"FASEB J"},{"key":"2026012222062070900_bib13","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1007\/s00418-013-1093-x","article-title":"GABAergic signaling in the pulmonary neuroepithelial body microenvironment: functional imaging in GAD67-GFP mice","volume":"140","author":"Schnorbusch","year":"2013","journal-title":"Histochem Cell Biol"},{"key":"2026012222062070900_bib14","doi-asserted-by":"crossref","first-page":"eaan8546","DOI":"10.1126\/science.aan8546","article-title":"Pulmonary neuroendocrine cells amplify allergic asthma responses","volume":"360","author":"Sui","year":"2018","journal-title":"Science"},{"key":"2026012222062070900_bib15","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1165\/rcmb.2004-0060OC","article-title":"Mucin is produced by Clara cells in the proximal airways of antigen-challenged mice","volume":"31","author":"Evans","year":"2004","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026012222062070900_bib16","doi-asserted-by":"crossref","first-page":"2069","DOI":"10.1016\/S0002-9440(10)64338-6","article-title":"Pathogenesis of mucous cell metaplasia in a murine asthma model","volume":"162","author":"Reader","year":"2003","journal-title":"Am J Pathol"},{"key":"2026012222062070900_bib17","first-page":"2914","article-title":"SPDEF is required for mouse pulmonary goblet cell differentiation and regulates a network of genes associated with mucus production","volume":"119","author":"Chen","year":"2009","journal-title":"J Clin Invest"},{"key":"2026012222062070900_bib18","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1164\/rccm.200811-1768OC","article-title":"Distinct roles of FOXA2 and FOXA3 in allergic airway disease and asthma","volume":"180","author":"Park","year":"2009","journal-title":"Am J Respir Crit Care Med"},{"key":"2026012222062070900_bib19","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1038\/nm1604","article-title":"A GABAergic system in airway epithelium is essential for mucus overproduction in asthma","volume":"13","author":"Xiang","year":"2007","journal-title":"Nat Med"},{"key":"2026012222062070900_bib20","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1165\/rcmb.2010-0109OC","article-title":"Prenatal nicotine exposure increases GABA signaling and mucin expression in airway epithelium","volume":"44","author":"Fu","year":"2011","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026012222062070900_bib21","doi-asserted-by":"crossref","first-page":"4542","DOI":"10.4049\/jimmunol.1101567","article-title":"Prenatal secondhand cigarette smoke promotes Th2 polarization and impairs goblet cell differentiation and airway mucus formation","volume":"187","author":"Singh","year":"2011","journal-title":"J Immunol"},{"key":"2026012222062070900_bib22","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/S0041-008X(03)00218-7","article-title":"Repeated episodes of ozone inhalation amplifies the effects of allergen sensitization and inhalation on airway immune and structural development in Rhesus monkeys","volume":"191","author":"Schelegle","year":"2003","journal-title":"Toxicol Appl Pharmacol"},{"key":"2026012222062070900_bib23","doi-asserted-by":"crossref","first-page":"15858","DOI":"10.1073\/pnas.0707413104","article-title":"Genome-wide profiling identifies epithelial cell genes associated with asthma and with treatment response to corticosteroids","volume":"104","author":"Woodruff","year":"2007","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026012222062070900_bib24","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1111\/1467-9868.00346","article-title":"A direct approach to false discovery rates","volume":"64","author":"Storey","year":"2002","journal-title":"J R Stat Soc Ser A Stat Soc"},{"key":"2026012222062070900_bib25","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1007\/978-1-62703-125-7_8","article-title":"Human nasal and tracheo-bronchial respiratory epithelial cell culture","volume":"945","author":"Fulcher","year":"2013","journal-title":"Methods Mol Biol"},{"key":"2026012222062070900_bib26","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1165\/rcmb.2008-0195OC","article-title":"Chronic intermittent mechanical stress increases MUC5AC protein expression","volume":"41","author":"Park","year":"2009","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026012222062070900_bib27","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1038\/labinvest.3700412","article-title":"Functional facets of the pulmonary neuroendocrine system","volume":"86","author":"Linnoila","year":"2006","journal-title":"Lab Invest"},{"key":"2026012222062070900_bib28","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1165\/rcmb.2006-0466OC","article-title":"Transcriptional profiling of mucociliary differentiation in human airway epithelial cells","volume":"37","author":"Ross","year":"2007","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026012222062070900_bib29","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1165\/rcmb.2013-0199OC","article-title":"Chemosensory functions for pulmonary neuroendocrine cells","volume":"50","author":"Gu","year":"2014","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026012222062070900_bib30","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1165\/rcmb.2015-0252OC","article-title":"IL-13 augments compressive stress-induced tissue factor expression in human airway epithelial cells","volume":"54","author":"Mitchel","year":"2016","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026012222062070900_bib31","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1165\/rcmb.2006-0180OC","article-title":"IL-13 and epidermal growth factor receptor have critical but distinct roles in epithelial cell mucin production","volume":"36","author":"Zhen","year":"2007","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026012222062070900_bib32","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1165\/rcmb.2006-0400OC","article-title":"IL-13 regulates cilia loss and foxj1 expression in human airway epithelium","volume":"37","author":"Gomperts","year":"2007","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026012222062070900_bib33","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1038\/s41598-017-18884-9","article-title":"IL-13 in LPS-induced inflammation causes Bcl-2 expression to sustain hyperplastic mucous cells","volume":"8","author":"Chand","year":"2018","journal-title":"Sci Rep"},{"key":"2026012222062070900_bib34","doi-asserted-by":"crossref","first-page":"36012","DOI":"10.1074\/jbc.M606895200","article-title":"A novel function of ionotropic \u03b3-aminobutyric acid receptors involving alveolar fluid homeostasis","volume":"281","author":"Jin","year":"2006","journal-title":"J Biol Chem"},{"key":"2026012222062070900_bib35","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1146\/annurev.physiol.70.113006.100441","article-title":"Regulation of airway mucin gene expression","volume":"70","author":"Thai","year":"2008","journal-title":"Annu Rev Physiol"},{"key":"2026012222062070900_bib36","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1002\/ppul.21219","article-title":"Familial neuroendocrine cell hyperplasia of infancy","volume":"45","author":"Popler","year":"2010","journal-title":"Pediatr Pulmonol"},{"key":"2026012222062070900_bib37","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1378\/chest.10-1304","article-title":"Neuroendocrine cell distribution and frequency distinguish neuroendocrine cell hyperplasia of infancy from other pulmonary disorders","volume":"139","author":"Young","year":"2011","journal-title":"Chest"},{"key":"2026012222062070900_bib38","doi-asserted-by":"crossref","first-page":"1840","DOI":"10.1016\/j.rmed.2005.10.024","article-title":"Neuroendocrine cell hyperplasia as an unusual form of interstitial lung disease","volume":"101","author":"Reyes","year":"2007","journal-title":"Respir Med"}],"container-title":["American Journal of Respiratory Cell and Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article-pdf\/60\/6\/687\/66465057\/ajrcmb_60_6_687.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article-pdf\/60\/6\/687\/66465057\/ajrcmb_60_6_687.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T03:09:55Z","timestamp":1769137795000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article\/60\/6\/687\/8430355"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,6,1]]},"references-count":38,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2019,6,1]]},"published-print":{"date-parts":[[2019,6,1]]}},"URL":"https:\/\/doi.org\/10.1165\/rcmb.2018-0179oc","relation":{},"ISSN":["1044-1549","1535-4989"],"issn-type":[{"value":"1044-1549","type":"print"},{"value":"1535-4989","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2019,6]]},"published":{"date-parts":[[2019,6,1]]}}}