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Institute","doi-asserted-by":"publisher","award":["AI149754"],"award-info":[{"award-number":["AI149754"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.atsjournals.org"],"crossmark-restriction":true},"published-print":{"date-parts":[[2023,2,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>CC16 is a protein mainly produced by nonciliated bronchial epithelial cells (BECs) that participates in host defense. Reduced CC16 protein concentrations in BAL and serum are associated with asthma susceptibility.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>Few studies have investigated the relationship between CC16 and asthma progression, and none has focused on BECs. In this study, we sought to determine if CC16 mRNA expression levels in BECs are associated with asthma severity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Association analyses between CC16 mRNA expression levels in BECs (242 asthmatics and 69 control subjects) and asthma-related phenotypes in Severe Asthma Research Program were performed using a generalized linear model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>Low CC16 mRNA expression levels in BECs were significantly associated with asthma susceptibility and asthma severity, high systemic corticosteroids use, high retrospective and prospective asthma exacerbations, and low pulmonary function. Low CC16 mRNA expression levels were significantly associated with high T2 inflammation biomarkers (fractional exhaled nitric oxide and sputum eosinophils). CC16 mRNA expression levels were negatively correlated with expression levels of Th2 genes (IL1RL1, POSTN, SERPINB2, CLCA1, NOS2, and MUC5AC) and positively correlated with expression levels of Th1 and inflammation genes (IL12A and MUC5B). A combination of two nontraditional T2 biomarkers (CC16 and IL-6) revealed four asthma endotypes with different characteristics of T2 inflammation, obesity, and asthma severity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings indicate that low CC16 mRNA expression levels in BECs are associated with asthma susceptibility, severity, and exacerbations, partially through immunomodulation of T2 inflammation. CC16 is a potential nontraditional T2 biomarker for asthma development and progression.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.202206-1230oc","type":"journal-article","created":{"date-parts":[[2022,9,6]],"date-time":"2022-09-06T11:19:29Z","timestamp":1662463169000},"page":"438-451","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":38,"title":["Low CC16 mRNA Expression Levels in Bronchial Epithelial Cells Are Associated with Asthma Severity"],"prefix":"10.1093","volume":"207","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1208-8658","authenticated-orcid":false,"given":"Xingnan","family":"Li","sequence":"first","affiliation":[{"name":"Division of Genetics, Genomics, and Precision Medicine, and"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7218-3246","authenticated-orcid":false,"given":"Stefano","family":"Guerra","sequence":"additional","affiliation":[{"name":"Asthma and Airway Disease Research Center, Department of Medicine, University of Arizona, Tucson, Arizona"}]},{"given":"Julie G.","family":"Ledford","sequence":"additional","affiliation":[{"name":"Asthma and Airway Disease Research Center, Department of Medicine, University of Arizona, Tucson, Arizona"}]},{"given":"Monica","family":"Kraft","sequence":"additional","affiliation":[{"name":"Asthma and Airway Disease Research Center, Department of Medicine, University of Arizona, Tucson, Arizona"}]},{"given":"Huashi","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Genetics, Genomics, and Precision Medicine, and"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6607-7797","authenticated-orcid":false,"given":"Annette T.","family":"Hastie","sequence":"additional","affiliation":[{"name":"Department of Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina"}]},{"given":"Mario","family":"Castro","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, and Sleep Medicine, University of Kansas School of Medicine, Kansas City, Kansas"}]},{"given":"Loren C.","family":"Denlinger","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Wisconsin School of Medicine & Public Health, Madison, Wisconsin"}]},{"given":"Serpil C.","family":"Erzurum","sequence":"additional","affiliation":[{"name":"Lerner Research Institute and the Respiratory Institute, Cleveland Clinic, Cleveland, Ohio"}]},{"given":"John V.","family":"Fahy","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, Sleep, and Allergy, Department of Medicine, University of California at San Francisco, San Francisco, California"}]},{"given":"Benjamin","family":"Gaston","sequence":"additional","affiliation":[{"name":"Wells Center for Pediatric Research and Riley Hospital for Children, Indiana University, Indianapolis, Indiana"}]},{"given":"Elliot","family":"Israel","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, Massachusetts"}]},{"given":"Nizar N.","family":"Jarjour","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Wisconsin School of Medicine & Public Health, Madison, Wisconsin"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9515-5731","authenticated-orcid":false,"given":"Bruce D.","family":"Levy","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, Massachusetts"}]},{"given":"David T.","family":"Mauger","sequence":"additional","affiliation":[{"name":"Department of Public Health Sciences, College of Medicine, Penn State University, Hershey, Pennsylvania"}]},{"given":"Wendy C.","family":"Moore","sequence":"additional","affiliation":[{"name":"Department of Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina"}]},{"given":"Joe","family":"Zein","sequence":"additional","affiliation":[{"name":"Lerner Research Institute and the Respiratory Institute, Cleveland Clinic, Cleveland, Ohio"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5917-4601","authenticated-orcid":false,"given":"Naftali","family":"Kaminski","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut; and"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4242-0164","authenticated-orcid":false,"given":"Sally E.","family":"Wenzel","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania"}]},{"given":"Prescott G.","family":"Woodruff","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, Sleep, and Allergy, Department of Medicine, University of California at San Francisco, San 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