Cigarette Smoke in Early Life Alters Airway Reactivity

描述（由申请人提供）：该项目的目的是阐明在生命早期关键发育窗口暴露于环境烟草烟雾（ETS）所引起的神经机制变化，并导致成人哮喘易感性和发生率增加。在子宫内或出生后早期发育期间接触ETS会增加以后生活中呼吸道疾病的发病率。早期生活中易感性增强的机制和确定易感性关键窗口的基础尚未得到很好的理解。在发育过程中，神经系统极易受到环境的影响，包括供应呼吸道的神经。在胎儿和出生后早期，气道神经支配与肺的发育同时迅速发育。鉴于发育过程的动态性和脆弱性，这一时期的形态形成可能对环境的损害非常敏感。P物质（Substance P， SP）是由气道感觉神经合成并释放的一种神经递质，在抗原或刺激性哮喘中起重要作用。SP可引发支气管哮喘症状，包括气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，我们假设早期暴露于ETS会永久改变气道神经元和气道壁中的SP水平。此外，我们假设这些变化是通过NGF介导的，并表现为神经反应性增加，进而促进气道高反应性和晚年对哮喘的易感性增加。具体目的是：1)通过测量气道神经支配神经元的SP和肺功能的动态变化，确定ETS易感性的关键窗口；2)确定关键发育时期NGF限制对ETS诱导的SP调节气道高反应性的影响。如果我们的假设是正确的，该研究将表明，在关键的暴露窗口期间，生长因子的表达是导致成人神经递质调节改变的原因。这些发现将为早期生活中ETS易感性的机制提供新的认识。

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.