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Updated: May 21, 2026
Isolation of Lung Retinoid-Containing Cells by Cell Sorting
Published on: April 11, 2025
Maternal smoking and the retinoid pathway in the developing lung
Sara E Manoli1, Lacey A Smith, Carrie A Vyhlidal
1Department of Medicine, Division of Pulmonary and Critical Care, Brigham and Women's Hospital, Boston, MA, USA.
Insights
Maternal smoking in mice led to defective lung alveolarization and altered retinoic acid signaling in offspring. Cigarette smoke components impaired retinoic acid response element activation, suggesting a link to pediatric lung disease.
Area of Science:
- Pulmonary Medicine
- Developmental Biology
- Toxicology
Background:
- Maternal smoking is a known risk factor for pediatric lung diseases, including asthma.
- Animal studies indicate maternal smoking can impair lung alveolarization in offspring.
- Retinoic acid signaling plays a crucial role in lung development and immune function, making it a potential mediator of smoking-induced lung damage.
Purpose of the Study:
- To investigate whether maternal cigarette smoke exposure disrupts retinoic acid pathway expression and function in a murine model.
- To determine if components of cigarette smoke directly affect retinoic acid signaling.
Main Methods:
- Female mice were exposed to cigarette smoke throughout pregnancy and lactation.
- Offspring lung tissue was analyzed for alveolarization defects (mean linear intercept) and retinoic acid pathway gene expression (quantitative PCR).
- In vitro experiments using A549 cells assessed the impact of lipid-soluble smoke components on retinoic acid response element activation.
Main Results:
- Offspring exposed to maternal smoking exhibited significantly increased mean linear intercepts, indicating defective alveolarization.
- mRNA and protein expression of key retinoic acid signaling elements (retinoic acid receptor alpha and beta) were significantly decreased in exposed offspring.
- Lipid-soluble cigarette smoke components significantly reduced retinoic acid-induced binding and activation of the retinoic acid receptor response element in cell culture.
Conclusions:
- Maternal cigarette smoking in mice results in abnormal lung alveolarization and altered retinoic acid pathway expression in offspring.
- In vitro findings demonstrate that cigarette smoke components can directly inhibit retinoic acid signaling.
- Disruption of retinoic acid signaling is a plausible mechanism contributing to pediatric lung dysfunction following maternal smoking exposure.
Background:
Maternal smoking is a risk factor for pediatric lung disease, including asthma. Animal models suggest that maternal smoking causes defective alveolarization in the offspring. Retinoic acid signaling modulates both lung development and postnatal immune function. Thus, abnormalities in this pathway could mediate maternal smoking effects. We tested whether maternal smoking disrupts retinoic acid pathway expression and functioning in a murine model.
Methods:
Female C57Bl/6 mice with/without mainstream cigarette smoke exposure (3 research cigarettes a day, 5 days a week) were mated to nonsmoking males. Cigarette smoke exposure continued throughout the pregnancy and after parturition. Lung tissue from the offspring was examined by mean linear intercept analysis and by quantitative PCR. Cell culture experiments using the type II cell-like cell line, A549, tested whether lipid-soluble cigarette smoke components affected binding and activation of retinoic acid response elements in vitro.
Results:
Compared to tobacco-naïve mice, juvenile mice with tobacco toxin exposure had significantly (P < 0.05) increased mean linear intercepts, consistent with an alveolarization defect. Tobacco toxin exposure significantly (P < 0.05) decreased mRNA and protein expression of retinoic acid signaling pathway elements, including retinoic acid receptor alpha and retinoic acid receptor beta, with the greatest number of changes observed between postnatal days 3-5. Lipid-soluble cigarette smoke components significantly (P < 0.05) decreased retinoic acid-induced binding and activation of the retinoic acid receptor response element in A549 cells.
Conclusions:
A murine model of maternal cigarette smoking causes abnormal alveolarization in association with altered retinoic acid pathway element expression in the offspring. An in vitro cell culture model shows that lipid-soluble components of cigarette smoke decrease retinoic acid response element activation. It is feasible that disruption of retinoic acid signaling contributes to the pediatric lung dysfunction caused by maternal smoking.
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