Abstract
BackgroundMaternal 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.MethodsFemale 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.ResultsCompared 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.ConclusionsA 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.
Highlights
Maternal smoking is an important risk factor for pediatric lung dysfunction, including asthma [1,2,3,4,5,6]
Our model showed that tobacco toxin exposure during development significantly (P = 0.009) increased mean linear intercept (MLI) at postnatal day 14 (P14), consistent with increased average distance between gas exchange elements in the distal lung, in these mice compared to age-matched tobacconaïve mice (Figure 1)
Since our in vitro model suggested that components of cigarette smoke might decrease retinoic acid (RA) signaling in lung cells, we examined our in vivo model of murine developmental tobacco toxin exposure for similar evidence of decreased RA pathway function by examining mRNA expression of RA-regulated genes in lung tissue from mice with developmental tobacco toxin exposure
Summary
Maternal smoking is an important risk factor for pediatric lung dysfunction, including asthma [1,2,3,4,5,6]. One possible pathway that could mediate some of the lung abnormalities caused by maternal smoking is the retinoic acid (RA) signaling pathway. Cigarette smoking causes abnormalities in retinol levels in rodents [26]. Several studies comparing serum retinol levels in smokers versus nonsmokers have not demonstrated statistically significant differences [30,31,32,33]. Retinoic acid signaling modulates both lung development and postnatal immune function. 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
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