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Club Cell protein 16 (CC16) is a key determinant of lung health, with low levels associated with impaired lung development, reduced lung function, and COPD. Cigarette smoking lowers CC16, but it is unknown whether maternal smoking leads to persistent CC16 deficiency from early life, thereby disrupting lung development and predisposing to COPD risk and progression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>CC16 expression was analyzed across 4 human cohorts, in plasma samples (COPDGene [n\u2009=\u20091062] and ECLIPSE [n\u2009=\u20092164]), nasal brushings (ALLIANCE [n\u2009=\u200963]), and peripheral lung sections (LTRC [n\u2009=\u200944]) from participants with and without a history of maternal smoking exposure. Lung histology and respiratory mechanics were assessed in WT and Cc16-\/- mice with and without maternal smoking exposure. Recombinant human (rh)CC16 effects on lung maturation were assessed in embryonic murine lung explants.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Maternal smoking was linked to reduced circulating and airway CC16 in COPD patients, controls, and a preclinical murine COPD model. In human adults, lower CC16 correlated with accelerated lung function decline and emphysema progression, while in children it was associated with obstructive physiology and early small airway impairment. In both mice and humans, maternal smoking-induced CC16 reduction was accompanied by greater epithelial injury (fibrosis, inflammation, apoptosis, and oxidative stress). In murine explants, smoking impaired lung branching, whereas rhCC16 restored branching via \u03b12-integrin binding.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Maternal smoking reduces CC16 levels, disrupting lung development in ways that predispose to lifelong impairment of lung function and worse COPD outcomes. Defining the mechanisms by which CC16 regulates lung maturation is essential for establishing reliable outcome measures and designing trials aimed at preventing early COPD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.202504-0854oc","type":"journal-article","created":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T16:32:38Z","timestamp":1759854758000},"page":"591-604","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":7,"title":["Maternal smoking and CC-16: implications for lung development and COPD across the lifespan"],"prefix":"10.1093","volume":"212","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4994-075X","authenticated-orcid":false,"given":"Joselyn","family":"Rojas-Quintero","sequence":"first","affiliation":[{"name":"Pulmonary Division, Department of Medicine, Baylor College of Medicine , Houston, TX,","place":["United States"]},{"name":"Pulmonary and Critical Care Medicine Division, Brigham and 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