Research Project
2741951
The deleterious effects of maternal smoking during pregnancy are all too well established. Maternal smoking is the major preventable cause of intrauterine growth retardation and prematurity. Perhaps less well appreciated, is the recent, overwhelming evidence, that smoking during pregnancy directly and adversely effects lung development. Respiratory problems associated with in utero tobacco exposure 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. Our preliminary data suggests that nicotine itself is one of the factors responsible for the changes in pulmonary function observed in neonates born to smoking mothers. In this application we propose to use the rhesus monkey to characterize the effects of chronic exposure to low levels of nicotine throughout pregnancy on lung development and subsequent pulmonary function. Whole animal studies will be complemented with in vitro studies to begin to determine the molecular mechanisms underlying nicotine's effect on lung. In preliminary studies we have demonstrated that exposure of pregnant rhesus monkeys to a nicotine dose consistent with that of smokers alters fetal airway development and that related effects can be produced in fetal monkey lung organ cultured. Immunohistochemistry shows wide expression of nicotinic receptors in developing lung and nicotine appears to alter the pattern of receptor expression. Preliminary data further suggests that some of the effects of nicotine, acting through nicotinic receptors, may be mediated by antagonism of the mitogenic effects of peptide growth factors. Thus we specifically propose to 1, Determine the basis for nicotine's actions by determining the time course and cell specific expression of nicotinic receptor subtype expression in fetal monkey lung; 2, Characterize the effect of fetal exposure to nicotine on lung development and function by functional, morphometric, immunohistochemical and molecular analysis; and 3, begin to determine the mechanism underlying nicotine's actions by use of fetal monkey lung organ culture. From these studies will come the first description of the effects of chronic nicotine exposure on lung function; a determination of the extent to which these effects are reversible; and a beginning understanding of the mechanisms underlying these effects. Definitive knowledge of the effects of nicotine on lung development would provide an important additional tool in smoking control and will begin to better explain the link between maternal smoking and altered neonatal respiratory function.
