Neuro-Immune Interactions in Developing Airways

哮喘的发病率在生命的头几年最高。在这段时间内，免疫功能和呼吸道控制机制都发生了发育变化。对呼吸道疾病模型的研究表明，当免疫/炎症事件发生在生命早期时，呼吸道控制的变化可能是显著的和持续的。这项提议的目标是描绘发育中的呼吸道中神经免疫相互作用，并定义这些过程出错的机制。这一提议的一个中心假设是，肺内的炎症反应导致呼吸道内神经元件的重塑。此外，当侮辱发生在遗传易感宿主的生命早期时，这种变化是最显著的。然而，当侮辱发生在免疫成熟正在进行的关键窗口期间时，这种对敏感宿主的需求可能会被克服。研究将在体内和体外进行，重点是不能在人类身上进行的工作。这一目标和这些假设将通过三个具体目标加以阐述。首先，当BALB/c小鼠在较小年龄时对过敏原致敏时，导致其呼吸道反应性更大增强的机制将被解决。在不同年龄产生的免疫/炎症反应将被定义并与T淋巴细胞亚群/细胞因子的表达作为年龄的函数有关。T细胞亚群及其产物的耗竭和重建将被用来定义早期过敏原致敏后更明显的高反应性的调节。第二，将在兔子和小鼠身上确定导致胆碱能功能改变的机制，这些改变正常发生，并由生命早期对变应原致敏而产生。这些研究将确定早期损伤是否增加含P物质(SP)的神经和/或呼吸道内SP受体的数量，并确定早期敏化是否改变通常下调胆碱能神经释放乙酰胆碱的M受体的功能和/或表达。第三，将在兔身上研究新生儿变应原致敏引起的神经介导的松弛反应丧失的机制。对可能导致这一松弛途径丧失的气道平滑肌功能的生化控制将是一个焦点。这些哺乳动物物种发育性呼吸道生物学的研究可以定义神经免疫机制，这些机制可能与婴儿和儿童发生的事件有关。

The incidence of asthma is highest in the first years of life. During this period of time, developmental changes in both immune function and mechanisms of airway control are occurring. Studies in models of airway disease suggest alterations in airway control may be pronounced and persistent when immunologic/inflammatory events occur early in life. The goal of this proposal is to delineate neuro-immune interactions in developing airways, and define the mechanisms via which these processes go awry. A central hypothesis of this proposal is that inflammatory reactions within the lung lead to remodeling of neural elements within airways. Furthermore, the alterations are most significant when the insult occurs early in life in genetically susceptible hosts. However, this need for a susceptible host may be overcome when the insult occurs during a critical window when immune maturation is ongoing. Studies will be performed in vivo and in vitro with emphasis on work that cannot be performed in humans. This goal and these hypotheses will be addressed via three specific aims. First, the mechanisms responsible for greater enhancement of airway responsiveness in BALB/c mice when they are sensitized to an allergen at younger ages will be addressed. The immune/inflammatory response generated at various ages will be defined and related to T- lymphocyte subsets/cytokine expression as a function of age. Depletion as well as reconstitution of T-cell subsets and their products will be used to define mediation of the more marked hyperresponsiveness noted after early allergen sensitization. Second, mechanisms responsible for alterations in cholinergic function that occur normally and are produced by sensitization to allergen early in life will be defined in rabbits and mice. These studies will determine if early insults increase the number of substance P (SP)-containing nerves and/or receptors for SP within airways, and define if early sensitization alters function and/or expression of the muscarinic autoreceptor that normally downregulates release of acetylcholine from cholinergic nerves. Third, mechanisms responsible for loss of neurally mediated relaxant responses that occur with neonatal allergen sensitization will be investigated in rabbits. Biochemical control of airway smooth muscle function that may be responsible for loss of this relaxant pathway will be a focus. These studies of developmental airway biology in mammalian species allow definition of neuro-immune mechanisms that may have relevance to events that occur in infants and small children.