Early life exposures and chronic lung disease

早期生活暴露和慢性肺病

• 批准号: 10579253
• 负责人: JESSE ROMAN
• 金额: $ 39万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10579253
• 关键词: Adult; Affect; Animal Model; Area; Asthma; Birth; Cell physiology; Child; Chronic; Chronic Disease; Chronic Obstructive Pulmonary Disease; Chronic lung disease; Country; Data; Deposition; Development; Disease; Embryo; Embryonic Development; Epigenetic Process; Event; Extracellular Matrix; Fibroblasts; Functional disorder; Gene Expression; Genes; Genetic; Genetically Modified Animals; Growth; Histone Acetylation; Image; In Vitro; Infection; Influenza A virus; Intervention; Left; Life; Link; Lung; Mediating; Modification; Morbidity - disease rate; Morphogenesis; Mus; Nicotine; Nicotine Dependence; Nicotinic Receptors; Obstructive Lung Diseases; Pathway interactions; Perinatal; Perinatal Exposure; Placenta; Plant alkaloid; Role; Source; Structure; Testing; Tobacco; Tobacco smoke; Virus Diseases; Work; airway hyperresponsiveness; design; developmental plasticity; early childhood; early life exposure; experimental study; in vivo; lung development; mortality; nicotine exposure; pharmacologic; postnatal; prenatal; promoter; tobacco exposure

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).

新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）是由早年的不良经历造成的。但具体原因和机制 造成这种长期事件的责任尚不清楚。我们探讨了生命早期接触烟草的情况 成分可能会促进适应不良，从而导致慢性阻塞性肺病的发展 成人。我们关注尼古丁，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）发挥作用。在早期的工作中，我们证明了曝光 小鼠胚胎肺外植体对尼古丁的影响导致肺分支形态发生异常。进一步的工作 揭示围产期尼古丁体内暴露导致年轻人气道结构和功能异常 肺部的特点是气道分支改变和周围细胞外基质 (ECM) 沉积增加 呼吸道；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 α7 nAChR 介导，从而揭示潜在的干预目标。与该提案更相关的是， 我们最近观察到，在胚胎发生期间开始长期接触尼古丁促进了肺结构 以及在以后的生活（成年期）中可检测到的功能异常。进一步的实验表明两者之间存在联系 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，年轻肺部的甲型流感感染也促进了长期影响，并且这些放大了 尼古丁的影响。这些观察结果得出这样的假设：从生命早期就开始接触尼古丁 通过激活 nAChRs 促进肺中长期存在的结构和功能异常，并通过 通过改变参与产前和产后肺部发育的ECM基因的表达 表观遗传作用机制。这些影响可以通过第二次打击（即病毒感染后早期）放大 出生）。该假设将在以下目标中得到检验：1) 确定 nAChR 在这些事件中的作用 使用遗传和药理学干预措施（目标 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的 ECM 基因表达（目的 2)、调查第二次打击（例如，产后早期病毒感染）对尼古丁引起的变化的影响 在成年哺乳动物的肺部（目标 3）。