Cigarette Smoke in Early Life Alters Airway Reactivity

生命早期的吸烟会改变气道反应性

• 批准号: 7074963
• 负责人: ZHONG-XIN WU
• 金额: $ 7.21万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-15 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7074963
• 关键词: asthma; developmental neurobiology; disease /disorder proneness /risk; early experience; environmental exposure; enzyme linked immunosorbent assay; genetically modified animals; immunocytochemistry; in situ hybridization; innervation; irritation /irritant; laboratory mouse; lung development; nerve growth factors; neuroregulation; passive smoking; protein structure function; respiratory epithelium; respiratory function; respiratory system; substance P

DESCRIPTION (provided by applicant): The goal of this project is to elucidate changes in neural mechanisms induced by exposure to environmental tobacco smoke (ETS) during critical developmental windows in early life and which lead to increased susceptibility and occurrence of adult asthma. Exposure to ETS in utero or during early postnatal development increases the incidence of respiratory illnesses later in life. The mechanisms of enhanced susceptibility in early life and the basis for defining critical windows of vulnerability are not well understood. The nervous system is highly susceptible to environmental influences during development, including the nerves supplying the airways. Airway innervation develops rapidly during fetal and early postnatal life in parallel with the developing lung. Given the dynamic and vulnerable nature of developmental processes, this period of morphogenesis is likely to be exquisitely sensitive to environmental insults. Substance P (SP), a neurotransmitter synthesized and released from airway sensory nerve, plays an important role in antigen or irritant-induced asthma. SP can trigger symptoms of bronchial asthma including airway smooth muscle constriction and acute inflammation. Interestingly, recent studies in our laboratory showed that nerve growth factor (NGF) generated by irritant exposure mediated the changes in SP phenotype and neuronal responses. Thus, we hypothesize that the levels of SP in the airway neurons and airway wall are permanently altered by exposure to ETS in early life. Further, we hypothesize that these changes are mediated through NGF and are manifest as increased neural responsiveness that in turn promotes airway hyperreactivity and increased susceptibility to asthma in later life. The specific aims are to 1). identify critical windows of susceptibility to ETS by measuring SP in neurons innervating the airway and dynamic changes in lung function, 2). determine the effects of NGF limitation during critical developmental periods in the ETS-induced modulation of SP regulating airway hyperreactivity. If our hypotheses are correct, the study will show that growth factor expression is responsible for altered neurotransmitter regulation in adults during critical exposure windows. The findings will provide new understanding about the mechanisms of ETS susceptibility during early life.

描述(由申请人提供)：本项目的目标是阐明在生命早期的关键发育窗口期暴露于环境烟草烟雾(ETS)所引起的神经机制的变化，这些变化导致成人哮喘易感性增加和发生。在子宫或出生后早期发育期间暴露于ETS会增加以后生活中呼吸系统疾病的发生率。早期生命中易感性增强的机制和确定脆弱性关键窗口的基础还没有被很好地理解。神经系统在发育过程中非常容易受到环境的影响，包括供应呼吸道的神经。随着肺的发育，呼吸道神经在胎儿和出生后早期迅速发育。鉴于发育过程的动态和脆弱性质，这一形态发生时期很可能对环境侮辱非常敏感。P物质(SP)是一种由呼吸道感觉神经合成和释放的神经递质，在抗原或刺激性哮喘中起重要作用。SP可引发哮喘症状，包括呼吸道平滑肌收缩和急性炎症。有趣的是，我们实验室最近的研究表明，刺激性暴露产生的神经生长因子(NGF)介导了SP表型和神经元反应的变化。因此，我们假设在生命早期暴露于ETS后，呼吸道神经元和气道壁中的SP水平会发生永久性的改变。此外，我们假设这些变化是通过NGF介导的，表现为神经反应性增强，进而促进呼吸道高反应性，并在以后的生活中增加哮喘的易感性。具体目标是：1)。通过测量支配呼吸道的神经元中的SP和肺功能的动态变化来确定ETS的易感性的关键窗口，2)。确定在ETS诱导的SP调节气道高反应性的关键发育期限制NGF的作用。如果我们的假设是正确的，这项研究将表明，在关键的暴露窗口期间，生长因子的表达对成年人神经递质调节的改变负责。这一发现将对早期ETS的易感性机制提供新的理解。