{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T22:14:26Z","timestamp":1793139266771,"version":"4.5.0"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2021,8,1]],"date-time":"2021-08-01T00:00:00Z","timestamp":1627776000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":["www.atsjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,8,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>Lymphangioleiomyomatosis (LAM) is a multisystem disease that causes lung cysts and respiratory failure. Loss of TSC (tuberous sclerosis complex) gene function results in a clone of \u201cLAM cells\u201d with dysregulated mTOR (mechanistic target of rapamycin) activity. LAM cells and fibroblasts form lung nodules that also contain mast cells, although their significance is unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To understand the mechanism of mast-cell accumulation and the role of mast cells in the pathogenesis of LAM.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Gene expression was examined using transcriptional profiling and qRT-PCR. Mast cell\/LAM nodule interactions were examined in vitro using spheroid TSC2-null cell\/fibroblast cocultures and in vivo using an immunocompetent Tsc2-null murine homograft model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>LAM-derived cell\/fibroblast cocultures induced multiple CXC chemokines in fibroblasts. LAM lungs had increased tryptase-positive mast cells expressing CXCRs (CXC chemokine receptors) (P\u2009&amp;lt;\u20090.05). Mast cells located around the periphery of LAM nodules were positively associated with the rate of lung function loss (P\u2009=\u20090.016). LAM spheroids attracted mast cells, and this process was inhibited by pharmacologic and CRISPR\/cas9 inhibition of CXCR1 and CXCR2. LAM spheroids caused mast-cell tryptase release, which induced fibroblast proliferation and increased LAM-spheroid size (1.36\u2009\u00b1\u20090.24\u2013fold; P\u2009=\u20090.0019). The tryptase inhibitor APC366 and sodium cromoglycate (SCG) inhibited mast cell\u2013induced spheroid growth. In vivo, SCG reduced mast-cell activation and Tsc2-null lung tumor burden (vehicle: 32.5.3%\u2009\u00b1\u200923.6%; SCG: 5.5%\u2009\u00b1\u20094.3%; P\u2009=\u20090.0035).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>LAM-cell\/fibroblast interactions attract mast cells where tryptase release contributes to disease progression. Repurposing SCG for use in LAM should be studied as an alternative or adjunct to mTOR inhibitor therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.202007-2854oc","type":"journal-article","created":{"date-parts":[[2021,4,21]],"date-time":"2021-04-21T18:17:10Z","timestamp":1619029030000},"page":"431-444","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":32,"title":["Mast-Cell Tryptase Release Contributes to Disease Progression in Lymphangioleiomyomatosis"],"prefix":"10.1093","volume":"204","author":[{"given":"Roya","family":"Babaei-Jadidi","sequence":"first","affiliation":[{"name":"Division of Respiratory Medicine, National Institute for Health Research Biomedical Research Centre and Biodiscovery Institute"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arundhati","family":"Dongre","sequence":"additional","affiliation":[{"name":"Division of Respiratory Medicine, National Institute for Health Research Biomedical Research Centre and Biodiscovery Institute"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanne","family":"Miller","sequence":"additional","affiliation":[{"name":"Division of Respiratory Medicine, National Institute for Health Research Biomedical Research Centre and Biodiscovery Institute"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcos","family":"Castellanos Uribe","sequence":"additional","affiliation":[{"name":"Nottingham Arabidopsis Stock Centre, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian D.","family":"Stewart","sequence":"additional","affiliation":[{"name":"Division of Respiratory Medicine, National Institute for Health Research Biomedical Research Centre and Biodiscovery Institute"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoe M.","family":"Thompson","sequence":"additional","affiliation":[{"name":"Division of Respiratory Medicine, National Institute for Health Research Biomedical Research Centre and Biodiscovery Institute"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdolrahman S.","family":"Nateri","sequence":"additional","affiliation":[{"name":"Cancer Genetics & Stem Cell Group, Division of Cancer and Stem Cells, Biodiscovery Institute, School of Medicine, University of Nottingham, Nottingham, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Bradding","sequence":"additional","affiliation":[{"name":"Department of Respiratory Sciences, Institute for Lung Health, University of Leicester, Leicester, United Kingdom"},{"name":"Respiratory Theme, National Institute for Health Research Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, United Kingdom; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean T.","family":"May","sequence":"additional","affiliation":[{"name":"Nottingham Arabidopsis Stock Centre, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debbie","family":"Clements","sequence":"additional","affiliation":[{"name":"Division of Respiratory Medicine, National Institute for Health Research Biomedical Research Centre and Biodiscovery Institute"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9837-2763","authenticated-orcid":false,"given":"Simon R.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Division of Respiratory Medicine, National Institute for Health Research Biomedical Research Centre and Biodiscovery Institute"},{"name":"National Centre for Lymphangioleiomyomatosis, Nottingham University Hospitals National Health Service Trust, Nottingham, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,8,15]]},"reference":[{"key":"2026030321595117700_bib1","doi-asserted-by":"crossref","first-page":"3807","DOI":"10.1172\/JCI58709","article-title":"Lymphangioleiomyomatosis: a wolf in sheep\u2019s clothing","volume":"122","author":"Henske","year":"2012","journal-title":"J Clin Invest"},{"key":"2026030321595117700_bib2","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1164\/rccm.201912-2445OC","article-title":"Single-cell transcriptomic analysis identifies a unique pulmonary lymphangioleiomyomatosis cell","volume":"202","author":"Guo","year":"2020","journal-title":"Am J Respir Crit Care Med"},{"key":"2026030321595117700_bib3","doi-asserted-by":"crossref","first-page":"109703","DOI":"10.1016\/j.mehy.2020.109703","article-title":"Pulmonary lymphangioleiomyomatosis originates in the pleural mesothelial cell population","volume":"141","author":"Clements","year":"2020","journal-title":"Med Hypotheses"},{"key":"2026030321595117700_bib4","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1016\/j.ccm.2016.04.002","article-title":"Lymphangioleiomyomatosis","volume":"37","author":"Johnson","year":"2016","journal-title":"Clin Chest Med"},{"key":"2026030321595117700_bib5","doi-asserted-by":"crossref","first-page":"806","DOI":"10.7326\/0003-4819-154-12-201106210-00008","article-title":"Recognition of tuberous sclerosis in adult women: delayed presentation with life-threatening consequences","volume":"154","author":"Seibert","year":"2011","journal-title":"Ann Intern Med"},{"key":"2026030321595117700_bib6","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1111\/dmcn.13352","article-title":"Causes of mortality in individuals with tuberous sclerosis complex","volume":"59","author":"Amin","year":"2017","journal-title":"Dev Med Child Neurol"},{"key":"2026030321595117700_bib7","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.1056\/NEJMoa1100391","article-title":"Efficacy and safety of sirolimus in lymphangioleiomyomatosis","volume":"364","author":"McCormack","year":"2011","journal-title":"N Engl J Med"},{"key":"2026030321595117700_bib8","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1136\/thoraxjnl-2017-210872","article-title":"Lung function response and side effects to rapamycin for lymphangioleiomyomatosis: a prospective national cohort study","volume":"73","author":"Bee","year":"2018","journal-title":"Thorax"},{"key":"2026030321595117700_bib9","doi-asserted-by":"crossref","first-page":"e0126025","DOI":"10.1371\/journal.pone.0126025","article-title":"Wild type mesenchymal cells contribute to the lung pathology of lymphangioleiomyomatosis","volume":"10","author":"Clements","year":"2015","journal-title":"PLoS One"},{"key":"2026030321595117700_bib10","doi-asserted-by":"crossref","first-page":"2051","DOI":"10.2353\/ajpath.2010.091239","article-title":"Lymphangioleiomyoma cells and lymphatic endothelial cells: expression of VEGFR-3 in lymphangioleiomyoma cell clusters","volume":"176","author":"Seyama","year":"2010","journal-title":"Am J Pathol"},{"key":"2026030321595117700_bib11","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1369\/0022155413489311","article-title":"Lymphatic endothelial differentiation in pulmonary lymphangioleiomyomatosis cells","volume":"61","author":"Davis","year":"2013","journal-title":"J Histochem Cytochem"},{"key":"2026030321595117700_bib12","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1016\/j.chest.2019.08.005","article-title":"Immunotherapy for lymphangioleiomyomatosis and tuberous sclerosis: progress and future directions","volume":"156","author":"Liu","year":"2019","journal-title":"Chest"},{"key":"2026030321595117700_bib13","doi-asserted-by":"crossref","first-page":"e98674","DOI":"10.1172\/jci.insight.98674","article-title":"TSC2-deficient tumors have evidence of T cell exhaustion and respond to anti-PD-1\/anti-CTLA-4 immunotherapy","volume":"3","author":"Liu","year":"2018","journal-title":"JCI Insight"},{"key":"2026030321595117700_bib14","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1165\/rcmb.2005-0387OC","article-title":"Tissue-specific renin\u2013angiotensin system in pulmonary lymphangioleiomyomatosis","volume":"35","author":"Valencia","year":"2006","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026030321595117700_bib15","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1002\/path.1780","article-title":"c-Kit immunophenotyping and metalloproteinase expression profiles of mast cells in interstitial lung diseases","volume":"206","author":"Edwards","year":"2005","journal-title":"J Pathol"},{"key":"2026030321595117700_bib16","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1002\/cjp2.162","article-title":"Evolution of lung pathology in lymphangioleiomyomatosis: associations with disease course and treatment response","volume":"6","author":"Miller","year":"2020","journal-title":"J Pathol Clin Res"},{"key":"2026030321595117700_bib17","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1111\/imr.12626","article-title":"The controversial role of mast cells in fibrosis","volume":"282","author":"Bradding","year":"2018","journal-title":"Immunol Rev"},{"key":"2026030321595117700_bib18","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1016\/j.cellsig.2004.09.017","article-title":"The action of the mast cell product tryptase on cyclooxygenase-2 (COX2) and subsequent fibroblast proliferation involves activation of the extracellular signal-regulated kinase isoforms 1 and 2 (erk1\/2)","volume":"17","author":"Frungieri","year":"2005","journal-title":"Cell Signal"},{"key":"2026030321595117700_bib19","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1164\/rccm.201604-0822OC","article-title":"Matrix metalloproteinase-1 activation contributes to airway smooth muscle growth and asthma severity","volume":"195","author":"Naveed","year":"2017","journal-title":"Am J Respir Crit Care Med"},{"key":"2026030321595117700_bib20","doi-asserted-by":"crossref","first-page":"8959","DOI":"10.1200\/JCO.2005.01.4910","article-title":"Macrophage and mast-cell invasion of tumor cell islets confers a marked survival advantage in non-small-cell lung cancer","volume":"23","author":"Welsh","year":"2005","journal-title":"J Clin Oncol"},{"key":"2026030321595117700_bib21","first-page":"A1421","article-title":"Mast cell recruitment in lymphangiomatosis and lung cystic destruction; opportunities for drug repurposing [abstract]","volume":"199","author":"Babaei-Jadidi","year":"2019","journal-title":"Am J Respir Crit Care Med"},{"key":"2026030321595117700_bib22","doi-asserted-by":"crossref","first-page":"L694","DOI":"10.1152\/ajplung.00204.2003","article-title":"Estradiol and tamoxifen stimulate lymphangiomyomatosis-associated angiomyolipoma cell growth and activate both genomic and non-genomic signaling pathways","volume":"286","author":"Yu","year":"2003","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2026030321595117700_bib23","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/S0002-9440(10)61720-8","article-title":"The generation and characterization of a cell line derived from a sporadic renal angiomyolipoma: use of telomerase to obtain stable populations of cells from benign neoplasms","volume":"159","author":"Arbiser","year":"2001","journal-title":"Am J Pathol"},{"key":"2026030321595117700_bib24","doi-asserted-by":"crossref","first-page":"154ra134","DOI":"10.1126\/scitranslmed.3003840","article-title":"Prevention of alveolar destruction and airspace enlargement in a mouse model of pulmonary lymphangioleiomyomatosis (LAM)","volume":"4","author":"Goncharova","year":"2012","journal-title":"Sci Transl Med"},{"key":"2026030321595117700_bib25","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1189\/jlb.68.1.38","article-title":"Adhesion of human lung mast cells to bronchial epithelium: evidence for a novel carbohydrate-mediated mechanism","volume":"68","author":"Sanmugalingam","year":"2000","journal-title":"J Leukoc Biol"},{"key":"2026030321595117700_bib26","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1002\/jlb.47.5.409","article-title":"Purification of tryptase from a human mast cell line","volume":"47","author":"Butterfield","year":"1990","journal-title":"J Leukoc Biol"},{"key":"2026030321595117700_bib27","doi-asserted-by":"crossref","first-page":"2281","DOI":"10.1038\/nprot.2013.143","article-title":"Genome engineering using the CRISPR-Cas9 system","volume":"8","author":"Ran","year":"2013","journal-title":"Nat Protoc"},{"key":"2026030321595117700_bib28","first-page":"19","article-title":"Mast cells in tumor growth: angiogenesis, tissue remodelling and immune-modulation","volume":"1796","author":"Maltby","year":"2009","journal-title":"Biochim Biophys Acta"},{"key":"2026030321595117700_bib29","doi-asserted-by":"crossref","first-page":"7372","DOI":"10.1016\/S0021-9258(17)38401-6","article-title":"Regulation of tryptase from human lung mast cells by heparin. Stabilization of the active tetramer","volume":"261","author":"Schwartz","year":"1986","journal-title":"J Biol Chem"},{"key":"2026030321595117700_bib30","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s12959-019-0194-8","article-title":"Protease-activated receptors (PARs): mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases","volume":"17","author":"Heuberger","year":"2019","journal-title":"Thromb J"},{"key":"2026030321595117700_bib31","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1111\/cea.12675","article-title":"Mast cells in asthma: state of the art","volume":"46","author":"Bradding","year":"2016","journal-title":"Clin Exp Allergy"},{"key":"2026030321595117700_bib32","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1146\/annurev-med-050715-104245","article-title":"Lymphangioleiomyomatosis: a monogenic model of malignancy","volume":"68","author":"Krymskaya","year":"2017","journal-title":"Annu Rev Med"},{"key":"2026030321595117700_bib33","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1152\/physrev.1997.77.4.1033","article-title":"Mast cells","volume":"77","author":"Metcalfe","year":"1997","journal-title":"Physiol Rev"},{"key":"2026030321595117700_bib34","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1038\/ni1158","article-title":"Mast cells in the development of adaptive immune responses","volume":"6","author":"Galli","year":"2005","journal-title":"Nat Immunol"},{"key":"2026030321595117700_bib35","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1084\/jem.20050959","article-title":"Low-dose irradiation promotes tissue revascularization through VEGF release from mast cells and MMP-9-mediated progenitor cell mobilization","volume":"202","author":"Heissig","year":"2005","journal-title":"J Exp Med"},{"key":"2026030321595117700_bib36","doi-asserted-by":"crossref","first-page":"1873","DOI":"10.1016\/j.intimp.2004.08.009","article-title":"Possible involvement of mast cells in collagen remodeling in the late phase of cutaneous wound healing in mice","volume":"4","author":"Iba","year":"2004","journal-title":"Int Immunopharmacol"},{"key":"2026030321595117700_bib37","doi-asserted-by":"crossref","first-page":"2366","DOI":"10.1096\/fj.06-5837fje","article-title":"Mast cells are required for normal healing of skin wounds in mice","volume":"20","author":"Weller","year":"2006","journal-title":"FASEB J"},{"key":"2026030321595117700_bib38","doi-asserted-by":"crossref","first-page":"18105","DOI":"10.1073\/pnas.0509148102","article-title":"Developmental checkpoints of the basophil\/mast cell lineages in adult murine hematopoiesis","volume":"102","author":"Arinobu","year":"2005","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026030321595117700_bib39","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1038\/mi.2009.136","article-title":"Advances in mast cell biology: new understanding of heterogeneity and function","volume":"3","author":"Moon","year":"2010","journal-title":"Mucosal Immunol"},{"key":"2026030321595117700_bib40","doi-asserted-by":"crossref","first-page":"20478","DOI":"10.1073\/pnas.0709651104","article-title":"Pulmonary CXCR2 regulates VCAM-1 and antigen-induced recruitment of mast cell progenitors","volume":"104","author":"Hallgren","year":"2007","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026030321595117700_bib41","doi-asserted-by":"crossref","first-page":"2271","DOI":"10.1002\/ijc.31613","article-title":"Low tumor infiltrating mast cell density confers prognostic benefit and reflects immunoactivation in colorectal cancer","volume":"143","author":"Mao","year":"2018","journal-title":"Int J Cancer"},{"key":"2026030321595117700_bib42","doi-asserted-by":"crossref","first-page":"2584243","DOI":"10.1155\/2018\/2584243","article-title":"Mast cell, the neglected member of the tumor microenvironment: role in breast cancer","volume":"2018","author":"Aponte-L\u00f3pez","year":"2018","journal-title":"J Immunol Res"},{"key":"2026030321595117700_bib43","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1038\/modpathol.3800094","article-title":"The presence of stromal mast cells identifies a subset of invasive breast cancers with a favorable prognosis","volume":"17","author":"Dabiri","year":"2004","journal-title":"Mod Pathol"},{"key":"2026030321595117700_bib44","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1136\/thoraxjnl-2019-213338","article-title":"Cross-sectional study of reversible airway obstruction in LAM: better evidence is needed for bronchodilator and inhaled steroid use","volume":"74","author":"Johnson","year":"2019","journal-title":"Thorax"},{"key":"2026030321595117700_bib45","doi-asserted-by":"crossref","first-page":"40","DOI":"10.3389\/fonc.2019.00040","article-title":"The CXCL8-CXCR1\/2 axis as a therapeutic target in breast cancer stem-like cells","volume":"9","author":"Ruffini","year":"2019","journal-title":"Front Oncol"},{"key":"2026030321595117700_bib46","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1038\/nri3690","article-title":"Mast cell secretory granules: armed for battle","volume":"14","author":"Wernersson","year":"2014","journal-title":"Nat Rev Immunol"},{"key":"2026030321595117700_bib47","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1172\/JCI114786","article-title":"Cloning and characterization of a second complementary DNA for human tryptase","volume":"86","author":"Miller","year":"1990","journal-title":"J Clin Invest"},{"key":"2026030321595117700_bib48","doi-asserted-by":"crossref","first-page":"1900","DOI":"10.1016\/j.intimp.2007.07.007","article-title":"Active monomers of human beta-tryptase have expanded substrate specificities","volume":"7","author":"Fukuoka","year":"2007","journal-title":"Int Immunopharmacol"},{"key":"2026030321595117700_bib49","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/S0163-7258(02)00237-1","article-title":"Role of protease-activated receptors in airway function: a target for therapeutic intervention?","volume":"95","author":"Lan","year":"2002","journal-title":"Pharmacol Ther"},{"key":"2026030321595117700_bib50","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/S0014-5793(97)01298-2","article-title":"Identification of potential activators of proteinase-activated receptor-2","volume":"417","author":"Fox","year":"1997","journal-title":"FEBS Lett"}],"container-title":["American Journal of Respiratory and Critical Care Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajrccm\/article-pdf\/204\/4\/431\/67012289\/ajrccm_204_4_431.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajrccm\/article-pdf\/204\/4\/431\/67012289\/ajrccm_204_4_431.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T03:00:25Z","timestamp":1772593225000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajrccm\/article\/204\/4\/431\/8492312"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8]]},"references-count":50,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,8,15]]},"published-print":{"date-parts":[[2021,8,15]]}},"URL":"https:\/\/doi.org\/10.1164\/rccm.202007-2854oc","relation":{},"ISSN":["1073-449X","1535-4970"],"issn-type":[{"value":"1073-449X","type":"print"},{"value":"1535-4970","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,8]]},"published":{"date-parts":[[2021,8]]},"assertion":[{"value":"2020-07-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-04-21","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-08-18","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}