Despite strong anti-smoking campaigns, in 2003, 11 % of American women smoked during pregnancy corresponding to over 400,000 smoke-exposed infants. Smoking during pregnancy leads to intrauterine growth retardation, premature delivery and has been estimated to cause 10% of infant and fetal mortality. Developing lung is particularly sensitive to maternal smoking and effects include decreased lung function, increased respiratory diseases and increased incidence of sudden infant death syndrome (SIDS). Given the unfortunate prevalence of smoking during pregnancy and the resulting serious consequences, it is of major importance to understand the mechanisms underlying smoking-induced changes in the newborn and to use this knowledge to prevent those changes. In our previous grant period we demonstrated that many of the effects of smoking during pregnancy on lung development are caused by nicotine crossing the placenta to interact with nicotinic receptors in the developing lung. We further demonstrated that prenatal nicotine exposure decreased pulmonary function of newborn monkeys and produced changes in connective tissue in their lungs. In exciting preliminary data we have found that maternal vitamin C supplementation can prevent some of the detrimental effects of prenatal nicotine exposure on lung function. In this application we will characterize how vitamin C supplementation prevents the effects of nicotine on lung function and further characterize the molecular mechanisms underlying the effects of prenatal nicotine exposure on lung function and development. Specifically we propose to: 1. Determine if vitamin C supplementation can prevent the effects of nicotine on lung function and development;2. Identify critical periods for the effects of nicotine and vitamin C on lung development;3. Characterize the mechanisms by which nicotine affects lung function and development;and 4. Use the newly developed Affymetrix rhesus monkey microarray chips to determine which effects of maternal smoking on gene expression in newborn lung are due to nicotine and which are due to other components of cigarette smoke. These studies will be approached using a non-human primate model in which timed pregnant rhesus monkeys are exposed to nicotine, and then pulmonary function of offspring studied at birth and correlated with changes in lung morphology and gene expression. Because of the close relationship between monkey lung and human lung these results will provide a clear path for clinical studies on the utility of vitamin C supplementation to prevent some of the effects of maternal smoking during pregnancy on offspring's lung function.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Lung Injury, Repair, and Remodeling Study Section (LIRR)
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Lin, Sara
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Oregon Health and Science University
Schools of Medicine
United States
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McEvoy, Cindy T; Spindel, Eliot R (2017) Pulmonary Effects of Maternal Smoking on the Fetus and Child: Effects on Lung Development, Respiratory Morbidities, and Life Long Lung Health. Paediatr Respir Rev 21:27-33
Spindel, Eliot R (2016) Cholinergic Targets in Lung Cancer. Curr Pharm Des 22:2152-9
Lo, Jamie O; Schabel, Matthias C; Roberts, Victoria H J et al. (2015) Vitamin C supplementation ameliorates the adverse effects of nicotine on placental hemodynamics and histology in nonhuman primates. Am J Obstet Gynecol 212:370.e1-8
Fu, Xiao Wen; Song, Ping Fang; Spindel, Eliot R (2015) Role of Lynx1 and related Ly6 proteins as modulators of cholinergic signaling in normal and neoplastic bronchial epithelium. Int Immunopharmacol 29:93-8
McEvoy, Cindy T; Schilling, Diane; Clay, Nakia et al. (2014) Vitamin C supplementation for pregnant smoking women and pulmonary function in their newborn infants: a randomized clinical trial. JAMA 311:2074-82
Song, Pingfang; Rekow, Stephen S; Singleton, Corey-Ayne et al. (2013) Choline transporter-like protein 4 (CTL4) links to non-neuronal acetylcholine synthesis. J Neurochem 126:451-61
Arraut, Amaryllis Maria Elpida; Frias, Antonio E; Hobbs, Theodore R et al. (2013) Fetal pulmonary arterial vascular impedance reflects changes in fetal oxygenation at near-term gestation in a nonhuman primate model. Reprod Sci 20:33-8
Fu, Xiao Wen; Rekow, Stephen S; Spindel, Eliot R (2012) The ly-6 protein, lynx1, is an endogenous inhibitor of nicotinic signaling in airway epithelium. Am J Physiol Lung Cell Mol Physiol 303:L661-8
Spindel, Eliot R (2012) Muscarinic receptor agonists and antagonists: effects on cancer. Handb Exp Pharmacol :451-68
Roberts, V H J; Räsänen, J P; Novy, M J et al. (2012) Restriction of placental vasculature in a non-human primate: a unique model to study placental plasticity. Placenta 33:73-6

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