EFFECTS OF PRENATAL EXPOSURE TO NICOTINE ON PRIMATE LUNG DEVELOPMENT

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。母亲吸烟是宫内发育迟缓和早产的主要可预防原因。最近有证据表明，怀孕期间吸烟会导致后代肺功能下降，呼吸系统疾病增加，婴儿猝死综合症（SIDS）发生率增加，这一点可能不太为人所知。因此，了解吸烟引起新生儿变化的机制是非常重要的。我们的初步数据表明，尼古丁是导致吸烟母亲所生新生儿肺功能变化的因素之一。在这个项目中，恒河猴被用来表征怀孕期间长期暴露于低水平尼古丁对肺部发育和功能的影响。初步研究表明，让怀孕的恒河猴接触与吸烟者相同剂量的尼古丁会改变胎儿气道发育。免疫组织化学显示尼古丁受体在发育中的肺部广泛表达，尼古丁似乎改变了受体的表达模式。本课题的目的是：1)通过测定胎儿猴肺中尼古丁受体亚型表达的时间过程和细胞特异性表达来确定尼古丁作用的基础；2)通过功能、形态计量学、免疫组织化学和分子分析表征胎儿暴露于尼古丁对肺发育和功能的影响；3)开始通过体外研究确定尼古丁作用的机制。这些研究将首次描述长期接触尼古丁对肺功能的影响，确定这些影响在多大程度上是可逆的，并初步了解这些影响的潜在机制。对尼古丁对肺部发育影响的明确认识将为控制吸烟提供一个重要的额外工具，并将为开发新的治疗方法提供新的途径，以阻止怀孕期间吸烟对胎儿发育的影响。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Maternal smoking is the major preventable cause of intrauterine growth retardation and prematurity. Perhaps less well appreciated is the recent evidence that smoking during pregnancy leads to decreased lung function, increased respiratory diseases and increased incidence of sudden infant death syndrome (SIDS) in the offspring. Thus it is of major importance to understand the mechanisms underlying smoking-induced changes in the newborn. Our preliminary data suggests that nicotine is one of the factors responsible for the changes in pulmonary function observed in neonates born to smoking mothers. In this project, rhesus monkeys are used to characterize the effects of chronic exposure to low levels of nicotine throughout pregnancy on lung development and function. Preliminary studies demonstrate that exposure of pregnant rhesus monkeys to a nicotine dose consistent with that of smokers alters fetal airway development. Immunohistochemistry shows wide expression of nicotinic receptors in developing lung and nicotine appears to alter the pattern of receptor expression. The purposes of this project are 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 in vitro studies. 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 lead to new approaches to develop therapies to block the effects of smoking during pregnancy on fetal development.