{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T04:09:14Z","timestamp":1770869354992,"version":"3.50.1"},"reference-count":53,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2016,4,1]],"date-time":"2016-04-01T00:00:00Z","timestamp":1459468800000},"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":[[2016,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Bone morphogenetic protein (BMP) signaling is important for correct lung morphogenesis, and there is evidence of BMP signaling reactivation in lung diseases. However, little is known about BMP signaling patterns in healthy airway homeostasis and inflammatory airway disease and during epithelial repair. In this study, a rhesus macaque (Macaca mulatta) model of allergic airway disease was used to investigate BMP signaling throughout the airways in health, disease, and regeneration. Stereologic quantification of immunofluorescent images was used to determine the expression of BMP receptor (BMPR) Ia and phosphorylated SMAD (pSMAD) 1\/5\/8 in the airway epithelium. A pSMAD 1\/5\/8 expression gradient was found along the airways of healthy juvenile rhesus macaques (n\u2009=\u20093, P\u2009&amp;lt;\u20090.005). Membrane-localized BMPRIa expression was also present in the epithelium of the healthy animals. After exposure to house dust mite allergen and ozone, significant down-regulation of nuclear pSMAD 1\/5\/8 occurs in the epithelium. When the animals were provided with a recovery period in filtered air, proliferating cell nuclear antigen, pSMAD 1\/5\/8, and membrane-localized BMPRIa expression were significantly increased in the epithelium of conducting airways (P\u2009&amp;lt;\u20090.005). Furthermore, in the asthmatic airways, altered BMPRIa localization was evident. Because of the elevated eosinophil presence in these airways, we investigated the effect of eosinophil-derived proteins on BMPRIa trafficking in epithelial cells. Eosinophil-derived proteins (eosinophil-derived neurotoxin, eosinophil peroxidase, and major basic protein) induced transient nuclear translocation of membrane-bound BMPRIa. This work mapping SMAD signaling in the airways of nonhuman primates highlights a potential mechanistic relationship between inflammatory mediators and BMP signaling and provides evidence that basal expression of the BMP signaling pathway may be important for maintaining healthy airways.<\/jats:p>","DOI":"10.1165\/rcmb.2015-0210oc","type":"journal-article","created":{"date-parts":[[2015,9,28]],"date-time":"2015-09-28T12:53:59Z","timestamp":1443444839000},"page":"562-573","source":"Crossref","is-referenced-by-count":10,"title":["SMAD Signaling in the Airways of Healthy Rhesus Macaques versus Rhesus Macaques with Asthma Highlights a Relationship Between Inflammation and Bone Morphogenetic Proteins"],"prefix":"10.1093","volume":"54","author":[{"given":"Therese M.","family":"Lynn","sequence":"first","affiliation":[{"name":"Biology Department, Maynooth University, County Kildare, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emer L.","family":"Molloy","sequence":"additional","affiliation":[{"name":"Biology Department, Maynooth University, County Kildare, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joanne C.","family":"Masterson","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Colorado Denver, Aurora, Colorado"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Senan F.","family":"Glynn","sequence":"additional","affiliation":[{"name":"Department of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard W.","family":"Costello","sequence":"additional","affiliation":[{"name":"Department of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark V.","family":"Avdalovic","sequence":"additional","affiliation":[{"name":"California National Primate Research Center, University of California, Davis, School of Veterinary Medicine, Davis, California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edward S.","family":"Schelegle","sequence":"additional","affiliation":[{"name":"California National Primate Research Center, University of California, Davis, School of Veterinary Medicine, Davis, California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa A.","family":"Miller","sequence":"additional","affiliation":[{"name":"California National Primate Research Center, University of California, Davis, School of Veterinary Medicine, Davis, California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dallas M.","family":"Hyde","sequence":"additional","affiliation":[{"name":"California National Primate Research Center, University of California, Davis, School of Veterinary Medicine, Davis, California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7197-4676","authenticated-orcid":false,"given":"Shirley","family":"O\u2019Dea","sequence":"additional","affiliation":[{"name":"Biology Department, Maynooth University, County Kildare, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2016,4,1]]},"reference":[{"key":"2026021122362786800_bib1","first-page":"1","article-title":"Pulmonary epithelium: cell types and functions. In: Proud D, editor. The pulmonary epithelium in health and disease. Chichester: John Wiley & Sons, Ltd.,","author":"Chang","year":"2008"},{"key":"2026021122362786800_bib2","doi-asserted-by":"crossref","first-page":"2000","DOI":"10.1164\/ajrccm.157.6.9707011","article-title":"Number and proliferation of basal and parabasal cells in normal human airway epithelium","volume":"157","author":"Boers","year":"1998","journal-title":"Am J Respir Crit Care Med"},{"key":"2026021122362786800_bib3","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.devcel.2009.12.010","article-title":"Preparing for the first breath: genetic and cellular mechanisms in lung development","volume":"18","author":"Morrisey","year":"2010","journal-title":"Dev Cell"},{"key":"2026021122362786800_bib4","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/S0925-4773(99)00325-1","article-title":"The molecular basis of lung morphogenesis","volume":"92","author":"Warburton","year":"2000","journal-title":"Mech Dev"},{"key":"2026021122362786800_bib5","doi-asserted-by":"crossref","first-page":"S12","DOI":"10.1513\/AnnalsATS.201207-036OT","article-title":"Molecular determinants of lung development","volume":"10","author":"Morrisey","year":"2013","journal-title":"Ann Am Thorac Soc"},{"key":"2026021122362786800_bib6","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1165\/ajrcmb.21.6.3807","article-title":"The attenuated fibroblast sheath of the respiratory tract epithelial-mesenchymal trophic unit","volume":"21","author":"Evans","year":"1999","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026021122362786800_bib7","doi-asserted-by":"crossref","first-page":"2065","DOI":"10.1172\/JCI45961","article-title":"The three R\u2019s of lung health and disease: repair, remodeling, and regeneration","volume":"121","author":"Beers","year":"2011","journal-title":"J Clin Invest"},{"key":"2026021122362786800_bib8","first-page":"S2","article-title":"Developmental responses to lung injury: repair or fibrosis","volume-title":"Fibrogenesis Tissue Repair","author":"Warburton","year":"2012"},{"key":"2026021122362786800_bib9","doi-asserted-by":"crossref","first-page":"4005","DOI":"10.1242\/dev.126.18.4005","article-title":"Bmp signaling regulates proximal-distal differentiation of endoderm in mouse lung development","volume":"126","author":"Weaver","year":"1999","journal-title":"Development"},{"key":"2026021122362786800_bib10","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1002\/dvdy.1231","article-title":"The bone morphogenic protein antagonist gremlin regulates proximal-distal patterning of the lung","volume":"222","author":"Lu","year":"2001","journal-title":"Dev Dyn"},{"key":"2026021122362786800_bib11","doi-asserted-by":"crossref","first-page":"2695","DOI":"10.1242\/dev.127.12.2695","article-title":"Bmp4 and Fgf10 play opposing roles during lung bud morphogenesis","volume":"127","author":"Weaver","year":"2000","journal-title":"Development"},{"key":"2026021122362786800_bib12","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1093\/carcin\/bgg100","article-title":"The mature bone morphogenetic protein-2 is aberrantly expressed in non-small cell lung carcinomas and stimulates tumor growth of A549 cells","volume":"24","author":"Langenfeld","year":"2003","journal-title":"Carcinogenesis"},{"key":"2026021122362786800_bib13","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1093\/hmg\/11.13.1517","article-title":"Functional analysis of bone morphogenetic protein type II receptor mutations underlying primary pulmonary hypertension","volume":"11","author":"Rudarakanchana","year":"2002","journal-title":"Hum Mol Genet"},{"key":"2026021122362786800_bib14","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1038\/nbt.2754","article-title":"Efficient generation of lung and airway epithelial cells from human pluripotent stem cells","volume":"32","author":"Huang","year":"2014","journal-title":"Nat Biotechnol"},{"key":"2026021122362786800_bib15","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1165\/rcmb.2005-0332OC","article-title":"Transdifferentiation of ciliated cells during repair of the respiratory epithelium","volume":"34","author":"Park","year":"2006","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026021122362786800_bib16","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1038\/nature12777","article-title":"Dedifferentiation of committed epithelial cells into stem cells in vivo","volume":"503","author":"Tata","year":"2013","journal-title":"Nature"},{"key":"2026021122362786800_bib17","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1002\/(SICI)1097-0177(199808)212:4<482::AID-AJA2>3.0.CO;2-D","article-title":". Mesenchyme specifies epithelial differentiation in reciprocal recombinants of embryonic lung and trachea","volume":"212","author":"Shannon","year":"1998","journal-title":"Dev Dyn"},{"key":"2026021122362786800_bib18","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1002\/jez.1401500202","article-title":"Induction in vitro of tracheal buds by pulmonary mesenchyme grafted on tracheal epithelium","volume":"150","author":"Alescio","year":"1962","journal-title":"J Exp Zool"},{"key":"2026021122362786800_bib19","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jez.1401750405","article-title":"Mammalian lung development: interactions in formation and morphogenesis of tracheal buds","volume":"175","author":"Wessells","year":"1970","journal-title":"J Exp Zool"},{"key":"2026021122362786800_bib20","doi-asserted-by":"crossref","first-page":"1899","DOI":"10.1242\/dev.034629","article-title":"Multiple roles for Sox2 in the developing and adult mouse trachea","volume":"136","author":"Que","year":"2009","journal-title":"Development"},{"key":"2026021122362786800_bib21","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/S0925-4773(99)00124-0","article-title":"Fibroblast growth factor interactions in the developing lung","volume":"86","author":"Lebeche","year":"1999","journal-title":"Mech Dev"},{"key":"2026021122362786800_bib22","first-page":"2352","article-title":"BMP signalling controls the construction of vertebrate mucociliary epithelia","volume":"142","author":"Cibois","year":"2015","journal-title":"Development"},{"key":"2026021122362786800_bib23","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":"2026021122362786800_bib24","doi-asserted-by":"crossref","first-page":"L125","DOI":"10.1152\/ajplung.00226.2012","article-title":"Accelerated structural decrements in the aging female rhesus macaque lung compared with males","volume":"304","author":"Herring","year":"2013","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2026021122362786800_bib25","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/S0041-008X(02)00026-1","article-title":"Repeated episodes of ozone inhalation attenuates airway injury\/repair and release of substance P, but not adaptation","volume":"186","author":"Schelegle","year":"2003","journal-title":"Toxicol Appl Pharmacol"},{"key":"2026021122362786800_bib26","first-page":"1131","article-title":"The remodelled tracheal basement membrane zone of infant rhesus monkeys after 6 months of recovery","volume-title":"Clin Exp Allergy","author":"Evans","year":"2004"},{"key":"2026021122362786800_bib27","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/S0002-9440(10)63973-9","article-title":"Allergic asthma induced in rhesus monkeys by house dust mite (Dermatophagoides farinae)","volume":"158","author":"Schelegle","year":"2001","journal-title":"Am J Pathol"},{"key":"2026021122362786800_bib28","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1080\/08977190801987166","article-title":"BMP4 induces an epithelial-mesenchymal transition-like response in adult airway epithelial cells","volume":"26","author":"Molloy","year":"2008","journal-title":"Growth Factors"},{"key":"2026021122362786800_bib29","doi-asserted-by":"crossref","first-page":"3016","DOI":"10.1002\/dvdy.22132","article-title":"Postnatal lung development of rhesus monkey airways: cellular expression of Clara cell secretory protein","volume":"238","author":"Coppens","year":"2009","journal-title":"Dev Dyn"},{"key":"2026021122362786800_bib30","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1164\/rccm.200506-848OC","article-title":"Vascular remodeling is airway generation-specific in a primate model of chronic asthma","volume":"174","author":"Avdalovic","year":"2006","journal-title":"Am J Respir Crit Care Med"},{"key":"2026021122362786800_bib31","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1084\/jem.137.6.1459","article-title":"Identification of a major basic protein in guinea pig eosinophil granules","volume":"137","author":"Gleich","year":"1973","journal-title":"J Exp Med"},{"key":"2026021122362786800_bib32","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1159\/000029979","article-title":"Human lung carcinoma cell line DLKP contains 3 distinct subpopulations with different growth and attachment properties","volume":"19","author":"McBride","year":"1998","journal-title":"Tumour Biol"},{"key":"2026021122362786800_bib33","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1016\/j.cellsig.2010.10.010","article-title":"Bone morphogenetic protein signalling in airway epithelial cells during regeneration","volume":"23","author":"Masterson","year":"2011","journal-title":"Cell Signal"},{"key":"2026021122362786800_bib34","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1164\/rccm.200709-1376OC","article-title":"Basal expression of bone morphogenetic protein receptor is reduced in mild asthma","volume":"177","author":"Kariyawasam","year":"2008","journal-title":"Am J Respir Crit Care Med"},{"key":"2026021122362786800_bib35","doi-asserted-by":"crossref","first-page":"1470","DOI":"10.1172\/JCI115155","article-title":"Human eosinophil major basic protein induces airway constriction and airway hyperresponsiveness in primates","volume":"87","author":"Gundel","year":"1991","journal-title":"J Clin Invest"},{"key":"2026021122362786800_bib36","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1016\/j.jaci.2012.07.025","article-title":"Human versus mouse eosinophils: \u201cthat which we call an eosinophil, by any other name would stain as red.\u201d","volume":"130","author":"Lee","year":"2012","journal-title":"J Allergy Clin Immunol"},{"key":"2026021122362786800_bib37","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.1242\/dev.122.6.1693","article-title":"Evidence from normal expression and targeted misexpression that bone morphogenetic protein (Bmp-4) plays a role in mouse embryonic lung morphogenesis","volume":"122","author":"Bellusci","year":"1996","journal-title":"Development"},{"key":"2026021122362786800_bib38","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1165\/ajrcmb.27.2.4779","article-title":"Activation of bone morphogenetic protein\/Smad signaling in bronchial epithelial cells during airway inflammation","volume":"27","author":"Rosendahl","year":"2002","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026021122362786800_bib39","doi-asserted-by":"crossref","first-page":"e41460","DOI":"10.1371\/journal.pone.0041460","article-title":"Activation of the canonical bone morphogenetic protein (BMP) pathway during lung morphogenesis and adult lung tissue repair","volume":"7","author":"Sountoulidis","year":"2012","journal-title":"PLoS One"},{"key":"2026021122362786800_bib40","first-page":"1","article-title":"The imperative balance of agonist and antagonist for BMP signalling driven adult tissue homeostasis","author":"Krause","year":"2014","journal-title":"Austin Biomark Diagn"},{"key":"2026021122362786800_bib41","doi-asserted-by":"crossref","first-page":"1776","DOI":"10.1126\/science.1100283","article-title":"A critical role for eosinophils in allergic airways remodeling","volume":"305","author":"Humbles","year":"2004","journal-title":"Science"},{"key":"2026021122362786800_bib42","first-page":"A6325","article-title":"Eosinophil mediated airway remodelling and the bone morphogenetic protein (BMP) pathway in asthma [abstract]","volume":"179","author":"Glynn","year":"2009","journal-title":"Am J Respir Crit Care Med"},{"key":"2026021122362786800_bib43","first-page":"223","article-title":"Bronchial hyperreactivity and eosinophil granule proteins","volume":"43","author":"Gleich","year":"1993","journal-title":"Agents Actions Suppl"},{"key":"2026021122362786800_bib44","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1002\/jcp.10275","article-title":"Bone morphogenetic protein-7 reduces the severity of colon tissue damage and accelerates the healing of inflammatory bowel disease in rats","volume":"196","author":"Maric","year":"2003","journal-title":"J Cell Physiol"},{"key":"2026021122362786800_bib45","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/rr169","article-title":"Growth factors in lung development and disease: friends or foe?","volume":"3","author":"Desai","year":"2002","journal-title":"Respir Res"},{"key":"2026021122362786800_bib46","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/79226","article-title":"Heterozygous germline mutations in BMPR2, encoding a TGF-\u03b2 receptor, cause familial primary pulmonary hypertension","volume":"26","author":"Lane","year":"2000","journal-title":"Nat Genet"},{"key":"2026021122362786800_bib47","doi-asserted-by":"crossref","first-page":"2578","DOI":"10.1073\/pnas.1319947111","article-title":"BMP signaling requires retromer-dependent recycling of the type I receptor","volume":"111","author":"Gleason","year":"2014","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026021122362786800_bib48","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1002\/ar.20824","article-title":"Postnatal development of the lamina reticularis in primate airways","volume":"293","author":"Evans","year":"2010","journal-title":"Anat Rec (Hoboken)"},{"key":"2026021122362786800_bib49","doi-asserted-by":"crossref","first-page":"318481","DOI":"10.1155\/2014\/318481","article-title":"TGF-\u03b2: An important mediator of allergic disease and a molecule with dual activity in cancer development","volume":"2014","author":"Tirado-Rodriguez","year":"2014","journal-title":"J Immunol Res"},{"key":"2026021122362786800_bib50","first-page":"66","article-title":"Regulation of epithelial proliferation by TGF-\u03b2","volume":"157","author":"Moses","year":"1991","journal-title":"Ciba Found Symp"},{"key":"2026021122362786800_bib51","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1164\/rccm.200609-1260OC","article-title":"Remodeling and airway hyperresponsiveness but not cellular inflammation persist after allergen challenge in asthma","volume":"175","author":"Kariyawasam","year":"2007","journal-title":"Am J Respir Crit Care Med"},{"key":"2026021122362786800_bib52","doi-asserted-by":"crossref","first-page":"3283","DOI":"10.1002\/eji.201344287","article-title":"Bone morphogenetic protein 4 inhibits liposaccharide-induced inflammation in the airway","volume":"44","author":"Li","year":"2014","journal-title":"Eur J Immunol"},{"key":"2026021122362786800_bib53","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1053\/j.gastro.2014.04.015","article-title":"Anti-inflammatory activity of bone morphogenetic protein signaling pathways in stomachs of mice","volume":"147","author":"Takabayashi","year":"2014","journal-title":"Gastroenterology"}],"container-title":["American Journal of Respiratory Cell and Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article-pdf\/54\/4\/562\/66824360\/ajrcmb_54_4_562.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article-pdf\/54\/4\/562\/66824360\/ajrcmb_54_4_562.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T03:40:14Z","timestamp":1770867614000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article\/54\/4\/562\/8469788"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,4,1]]},"references-count":53,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2016,4,1]]},"published-print":{"date-parts":[[2016,4,1]]}},"URL":"https:\/\/doi.org\/10.1165\/rcmb.2015-0210oc","relation":{},"ISSN":["1044-1549","1535-4989"],"issn-type":[{"value":"1044-1549","type":"print"},{"value":"1535-4989","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2016,4]]},"published":{"date-parts":[[2016,4,1]]}}}