{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:33:33Z","timestamp":1792787613704,"version":"4.5.0"},"reference-count":0,"publisher":"American Society for Clinical Investigation","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["R01 HL171622-01A1\/04"],"award-info":[{"award-number":["R01 HL171622-01A1\/04"]}]},{"name":"National Institutes of Health","award":["R01HL077328"],"award-info":[{"award-number":["R01HL077328"]}]},{"name":"National Institutes of Health","award":["R03HL095440"],"award-info":[{"award-number":["R03HL095440"]}]},{"name":"Ministero dell'Universit\u00e0 e della Ricerca","award":["PRIN 2022MMSBKL"],"award-info":[{"award-number":["PRIN 2022MMSBKL"]}],"id":[{"id":"https:\/\/ror.org\/0341vw408","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>Sex-specific mechanisms in chronic obstructive pulmonary disease (COPD) remain poorly defined. Sphingolipids are bioactive mediators that regulate airway epithelial integrity, inflammation, and bronchial smooth muscle tone, and their dysregulation contributes to airway hyperresponsiveness. We tested whether sphingolipid metabolism is regulated by sex in COPD. Lung tissue and paired plasma from female and male never-smoking controls (NSC), ever-smoking controls (SC), and COPD subjects were analyzed for sphingolipid enzyme expression and metabolite levels. Bronchial rings from mice and human bronchial smooth muscle cells (HBSMCs) were exposed to estradiol or cigarette smoke extract (CSE) \u00b1 ceramidase or sphingosine kinase inhibitors. Expression of sphingolipid regulators ASAH1 and ORMDL3 was increased in COPD airways, significantly higher in women, and correlated with airway smooth muscle remodeling. Plasma from females with COPD showed increased sphingosine-1-phosphate (S1P), whereas males exhibited higher ceramide levels. Female mice displayed greater CSE-induced bronchial reactivity, attenuated by sphingosine kinase inhibition. In male-donor HBSMCs, estradiol increased ASAH1, ORMDL3, S1P, and smooth muscle protein expression and enhanced contractility. CSE further augmented molecular responses in estradiol-treated cells but reduced collagen-gel contraction, whereas ceramidase inhibition attenuated estradiol-dependent effects. These findings suggest that estrogen-dependent alterations in sphingolipid metabolism contribute to airway hyperreactivity and remodeling in females with COPD.<\/jats:p>","DOI":"10.1172\/jci.insight.208692","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T16:01:06Z","timestamp":1790092866000},"source":"Crossref","is-referenced-by-count":0,"title":["Sphingolipid metabolism contributes to sex dimorphism in COPD pathogenesis"],"prefix":"10.1172","author":[{"given":"Elisabetta","family":"Granato","sequence":"first","affiliation":[{"name":"Department of Pharmacy, University of Naples Federico II, Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyun","family":"Wang","sequence":"additional","affiliation":[{"name":"Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joselyn","family":"Rojas-Quintero","sequence":"additional","affiliation":[{"name":"Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ida","family":"Cerqua","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Naples Federico II, Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott A.","family":"Ochsner","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeff Thomas","family":"Kue","sequence":"additional","affiliation":[{"name":"Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Cecchetto","sequence":"additional","affiliation":[{"name":"Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maor","family":"Sauler","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5343-103X","authenticated-orcid":true,"given":"Farrah","family":"Kheradmand","sequence":"additional","affiliation":[{"name":"Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0644-7754","authenticated-orcid":true,"given":"Joshua","family":"Malo","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Arizona, Tucson, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiorentina","family":"Roviezzo","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Naples Federico II, Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Petrache","sequence":"additional","affiliation":[{"name":"Department of Medicine, National Jewish Health and University of Colorado, Denver, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Polverino","sequence":"additional","affiliation":[{"name":"Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2026,9,22]]},"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/insight.jci.org\/articles\/view\/208692\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T16:01:08Z","timestamp":1790092868000},"score":1,"resource":{"primary":{"URL":"http:\/\/insight.jci.org\/articles\/view\/208692"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,22]]},"references-count":0,"alternative-id":["10.1172\/jci.insight.208692"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.208692","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,22]]}}}