Early life exposures and chronic lung disease

新的数据表明，慢性阻塞性肺疾病的发展受到很大影响， (and也许是预先确定的）由早期生活中的不利暴露所决定。然而，确切的原因和机制 对这些长期事件负责的人仍不清楚。我们探讨了早年接触烟草 成分可能会促进适应不良，导致慢性阻塞性肺病的发展， 成年人了我们把重点放在尼古丁上，因为这种烟草植物生物碱很容易穿过胎盘并影响细胞 通过激活烟碱乙酰胆碱受体（nAChR）发挥功能。在早期的研究中，我们发现 胚胎鼠肺外植体的尼古丁导致异常的肺分支形态发生。进一步工作 研究表明，出生前后体内尼古丁暴露导致年轻人气道结构和功能异常， 肺特征为气道分支改变和周围细胞外基质（ECM）沉积增加 这些变化与气道高反应性有关。值得注意的是，这些影响被发现， 通过乙酰胆碱受体介导，从而揭示潜在的干预目标。与这项提议更相关的是， 我们最近观察到，从胚胎发育期开始长期暴露于尼古丁， 以及在以后的生活（成年）中可检测到的功能异常。进一步的实验表明， 这些变化和ECM基因通过表观遗传作用机制的异常表达。最后我们 观察到，甲型流感病毒感染的年轻肺部也促进了长期的影响，这些放大了 尼古丁的影响这些观察结果导致了一个假设，即在生命早期就开始接触尼古丁。 通过激活nAChR促进肺中长期存在的结构和功能异常， ECM基因表达的改变涉及出生前和出生后的肺发育， 表观遗传作用机制。这些效果可以通过第二次击中（即，病毒感染后早期 出生）。这一假设将在以下目的中进行检验：1）确定nAChR在这些事件中的作用 使用遗传和药理学干预（目的1），检查尼古丁依赖性，基因特异性， 启动子相关的表观遗传修饰调节原代肺成纤维细胞中ECM基因的表达（Aim 2），并调查第二次打击的影响（例如，出生后早期病毒感染）对尼古丁诱导的变化的影响 在成年哺乳动物肺中（目标3）。

Emerging data suggest that the development of chronic obstructive lung diseases is greatly influenced (and perhaps pre-determined) by adverse exposures in early life. However, the exact causes and mechanisms responsible for such long-lasting events remain unclear. We explored how early life exposure to tobacco components might promote maladaptions that lead to the development of chronic obstructive lung disease in the adult. We focused on nicotine as this tobacco plant alkaloid readily traverses the placenta and impacts cell functions via activation of nicotinic acetylcholine receptors (nAChRs). In earlier work, we showed that exposure of embryonic murine lung explants to nicotine resulted in aberrant lung branching morphogenesis. Further work revealed that peri-natal nicotine exposure in vivo resulted in abnormal airway structure and function in the young lung characterized by alterations in airway branching and increased ext racellular matrix (ECM) deposition around the airways; these changes were associated with airway hyperreactivity. Notably, these effects were found to be mediated via  nAChRs, thereby unveiling potential targets for intervention. More relevant to this proposal, we recently observed that chronic exposure to nicotine starting during embryogenesis promoted lung structural and functional abnormalities detectable later in life (adulthood). Further experiments suggested a link between these changes and aberrant expression of ECM genes via epigenetic mechanisms of action. Finally, we observed that Influenza A infection of the young lung also promoted long-lasting effects, and these amplified the effects of nicotine. These observations led to the hypothesis that exposure to nicotine starting in early life promotes long-standing structural and functional abnormalities in lung through the activation of nAChRs, and via alterations in the expression of ECM genes involved in pre-natal and post-natal lung development through epigenetic mechanisms of action. These effects can be amplified by a second hit (i.e., viral infection early after birth). This hypothesis will be tested in aims designed to: 1) Determine the role of nAChRs in these events using genetic and pharmacological interventions (Aim 1), Examine the nicotine-dependent, gene-specific, promoter-associated epigenetic modifications regulating ECM gene expression in primary lung fibroblasts (Aim 2), and Investigate the impact of a second hit (e.g., early post-natal viral infection) on nicotine-induced changes in the adult mammalian lung (Aim 3).