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: 7220039
• 负责人: ZHONG-XIN WU
• 金额: $ 7.11万
• 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 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7220039
• 关键词: Acute; Adult; Adult asthma; Affect; Animals; Antigens; Asthma; Child; Condition; Constriction procedure; Coughing; Development; Developmental Process; Elderly; Embryonic Development; Environmental Risk Factor; Environmental Tobacco Smoke; Epidemiologic Studies; Exposure to; Goals; Growth; Growth Factor; Incidence; Individual; Infant; Inflammation; Irritants; Laboratories; Lead; Life; Link; Lung; Measures; Mediating; Morphogenesis; Nature; Nerve; Nerve Growth Factors; Nervous system structure; Neurons; Neuropeptides; Neurotransmitters; Ozone; Passive Smoking; Pathogenesis; Phenotype; Play; Predisposing Factor; Predisposition; Pregnancy; Production; Regulation; Research; Respiratory physiology; Role; Substance P; Symptoms; Wheezing; afferent nerve; age group; airway hyperresponsiveness; airway inflammation; airway obstruction; base; cigarette smoking; critical developmental period; design; fetal; in utero; maternal cigarette smoking; mature animal; nerve supply; neuromechanism; postnatal; relating to nervous system; research study; respiratory; respiratory smooth muscle; response

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）：本项目的目的是阐明在生命早期的关键发育窗口期间暴露于环境烟草烟雾（ETS）诱导的神经机制的变化，这些变化导致成人哮喘的易感性和发生率增加。在子宫内或出生后早期发育期间暴露于ETS会增加日后呼吸道疾病的发病率。人们对生命早期易感性增强的机制以及确定脆弱性临界窗口的依据还没有很好的了解。神经系统在发育过程中极易受到环境影响，包括供应气道的神经。在胎儿期和出生后早期，气道神经支配与肺的发育平行地迅速发育。鉴于发育过程的动态和脆弱性，这一时期的形态发生可能是非常敏感的环境侮辱。P物质（SP）是由气道感觉神经合成和释放的神经递质，在抗原或刺激物诱发的哮喘中起重要作用。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SP表型和神经元反应的变化。因此，我们推测，在气道神经元和气道壁的SP水平永久改变暴露于ETS在生命早期。此外，我们假设这些变化是通过神经生长因子介导的，表现为神经反应性增加，反过来又促进气道高反应性和增加晚年哮喘的易感性。具体目标是1）。通过测量支配气道的神经元中的SP和肺功能的动态变化来确定对ETS易感性的关键窗口，2）。确定在关键发育期，在ETS诱导的SP调节气道高反应性的调节中，NGF限制的影响。如果我们的假设是正确的，这项研究将表明，生长因子的表达是负责改变神经递质调节成人在关键暴露窗口。这一发现将为早期ETS易感性的机制提供新的认识。