Early life exposures and chronic lung disease

新出现的数据表明，慢性阻塞性肺疾病的发展受到很大影响。 (也许是预先决定的)由早年的不良暴露所致。然而，确切的原因和机制 对如此持久的事件负有责任的人目前仍不清楚。我们探索了早年接触烟草是如何 成分可能促进适应不良，从而导致慢性阻塞性肺疾病的发展 成年人。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。 通过激活烟碱型乙酰胆碱受体(NAChRs)发挥作用。在早期的工作中，我们展示了这种暴露 胚胎小鼠肺外植体对尼古丁的作用可导致肺分支形态发生异常。进一步工作 研究表明，围产期体内暴露尼古丁会导致年轻人的呼吸道结构和功能异常 以呼吸道分支改变和周围细胞外基质(ECM)沉积增加为特征的肺 这些改变与呼吸道高反应性有关。值得注意的是，这些影响被发现 通过nAChRs进行调节，从而揭示了潜在的干预目标。与这项提议更相关的是， 我们最近观察到，在胚胎发育期间开始长期接触尼古丁会促进肺结构 以及在成年后(成年)可检测到的功能异常。进一步的实验表明， 这些变化和ECM基因的异常表达通过表观遗传作用机制。最后，我们 观察到，年轻肺部感染甲型流感也促进了长期效应，这些增强了 尼古丁的影响。这些观察结果导致了一种假设，即从生命早期就开始接触尼古丁 通过激活nAChRs促进肺内长期的结构和功能异常，并通过 细胞外基质基因在出生前和出生后肺发育中的表达变化 表观遗传作用机制。这些影响可以通过第二次打击而放大(即在感染病毒后早期 出生)。这一假说将在旨在：1)确定nAChRs在这些事件中的作用的目标中得到验证 使用遗传和药物干预(目标1)，检查尼古丁依赖、基因特异性、 启动子相关的表观遗传修饰调控原代肺成纤维细胞ECM基因表达(目的 2)，并调查第二次打击(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).