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Early life exposures and chronic lung disease

早期生活暴露和慢性肺病

基本信息

批准号：
9887817
负责人：
JESSE ROMAN
金额：
$ 39万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
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/9887817
关键词：
Adult Affect Animal Model Area Asthma Birth Cell physiology Child Chronic Chronic Disease Chronic Obstructive Airway 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 Lead Left Life Link Lung Mediating Modification Morbidity - disease rate Morphogenesis Mus Nicotine Nicotine Dependence Nicotinic Receptors Obstructive Lung Diseases Pathway interactions Perinatal Perinatal Exposure Pharmacology 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 prenatal promoter tobacco exposure

项目摘要

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).

新出现的数据表明，慢性阻塞性肺病的发展受到很大影响