Abstract Background Lung function trajectories in early life predict long-term respiratory health, including the risk of COPD. Club Cell protein 16 (CC16) is crucial for lung health, and low levels are linked to impaired lung development and reduced lung function throughout life. Cigarette smoking reduces CC16, but it remains unclear whether in utero maternal smoking causes persistent CC16 deficiency from early life, potentially disrupting lung development and increasing COPD risk and progression. Methods CC16 expression was analyzed across 4 human cohorts, in plasma samples (COPDGene n = 1,062 and ECLIPSE n = 2,164), nasal brushings (ALLIANCE n = 63), and peripheral lung sections (LTRC n = 44) from participants with and without a history of in utero maternal smoking exposure. For COPDGene, bivariate analyses assessed lnCC16 with maternal smoking, using generalized linear models adjusted for age, sex, race, smoking, pack-years, and income. For ECLIPSE, linear models adjusted for age, sex, pack-years, education, and race evaluated baseline lnCC16 with %FEV1pred or % emphysema, and 1-year lnCC16 with %FEV1pred. For ALLIANCE, bivariate and adjusted linear models evaluated CC16 with smoking exposure and lung function. For LTRC, ANOVAs with post-hoc tests analyzed data. Results In COPDGene, maternal smoking was linked to lower lnCC16 levels in SC and COPD subjects, even after adjusting for current smoking (F = 10.41, P 0.0001; SC: F = 5.10, P = 0.024; COPD: F = 23.04, P 0.0001). Each SD decrease in lnCC16 correlated with a 172 mL FEV1 drop, exceeding the 100 mL Minimal Clinically Important Difference (MCID). Data was confirmed using multinominal logistic regression in ECLIPSE cohort, demonstrating accelerated decline in lung function when CC16 levels are initially lower. In ALLIANCE, higher CC16 expression levels were seen in kids without passive smoke exposure in childhood. In 63 wheezing children, lower nasal SCGB1A1 tied to reduced FEV1/FVC%pred and FEF25-75%pred. In LTRC, %CC16+ lung epithelial cells were consistently decreased in maternal smoke-exposed subjects, and strongly correlated with %FEV1pred, FEV1/FVC, DLCO, and inversely with % emphysema. Conclusions This evidence indicates that individuals exposed to in utero maternal smoking exhibit persistently reduced pulmonary and circulating CC16 levels, impaired lung function, heightened epithelial cell injury, and worse COPD outcomes in adulthood. These findings position CC16 as both a robust biomarker of lifelong lung health and a promising therapeutic target for preventing or mitigating COPD progression. This abstract is funded by: RO1 HL149744 and R01 HL171622.
Rojas-Quintero et al. (Fri,) studied this question.