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Maternal smoking and CC-16: implications for lung development and COPD across the lifespan
Joselyn Rojas-Quintero1,2, Rosa Faner3, Chia-Ying Chiu4
1Pulmonary Division, Department of Medicine, Baylor College of Medicine, Houston, TX, United States.
Insights
Maternal smoking reduces Club Cell protein 16 (CC16), impairing lung development and increasing COPD risk. This early-life deficiency leads to lifelong respiratory problems and worse disease outcomes.
Area of Science:
- Pulmonary Medicine
- Developmental Biology
- Environmental Health
Background:
- Early-life lung function predicts long-term respiratory health and COPD risk.
- Club Cell protein 16 (CC16) is vital for lung health; low levels correlate with impaired lung development, reduced lung function, and COPD.
- Maternal smoking is known to lower CC16, but its impact on early-life CC16 levels and subsequent COPD risk is unclear.
Purpose of the Study:
- To investigate the persistent effects of maternal smoking on CC16 levels from early life.
- To determine if maternal smoking-induced CC16 deficiency disrupts lung development and predisposes to COPD.
- To explore the mechanisms linking CC16 to lung maturation and COPD progression.
Main Methods:
- CC16 expression was analyzed in plasma, nasal brushings, and lung tissue from human cohorts (COPDGene, ECLIPSE, ALLIANCE, LTRC).
- Lung histology and respiratory mechanics were assessed in wild-type and Cc16 knockout mice exposed to maternal smoking.
- The effect of recombinant human CC16 (rhCC16) on lung maturation was studied in embryonic murine lung explants.
Main Results:
- Maternal smoking was associated with reduced CC16 in humans and mice, correlating with accelerated lung function decline and emphysema progression in adults.
- In children, low CC16 was linked to obstructive physiology and small airway impairment.
- Maternal smoking-induced CC16 reduction led to increased epithelial injury, and in mice, impaired lung branching, which rhCC16 could restore.
Conclusions:
- Maternal smoking causes a persistent reduction in CC16, disrupting lung development and increasing lifelong susceptibility to COPD.
- Understanding CC16's role in lung maturation is crucial for developing interventions to prevent early COPD.
- This study highlights the long-term respiratory consequences of in utero smoke exposure mediated by CC16 deficiency.
Rationale:
Early-life lung function trajectories predict long-term respiratory health, including COPD risk. 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.
Methods:
CC16 expression was analyzed across 4 human cohorts, in plasma samples (COPDGene [n = 1062] and ECLIPSE [n = 2164]), nasal brushings (ALLIANCE [n = 63]), and peripheral lung sections (LTRC [n = 44]) 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.
Results:
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 α2-integrin binding.
Conclusions:
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.
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