Neuro-Immune Interactions in Developing Airways

哮喘的发病率在生命的头几年是最高的。在此期间，免疫功能和气道控制机制都发生了发育变化。气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，气道控制的改变可能是明显和持续的。本提案的目标是描述发育中的气道中的神经免疫相互作用，并定义这些过程出错的机制。该提议的一个中心假设是，肺内的炎症反应导致气道内神经元件的重塑。此外，在遗传易感的宿主中，当这种侮辱发生在生命早期时，这种改变最为显著。然而，这种对易感宿主的需求可能会在免疫成熟的关键窗口期发生时被克服。研究将在体内和体外进行，重点是不能在人体中进行的工作。这一目标和这些假设将通过三个具体目标来解决。首先，当BALB/c小鼠在年轻时对过敏原致敏时，气道反应性增强的机制将被解决。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/细胞因子表达作为年龄的函数相关。t细胞亚群及其产物的耗损和重构将用于确定早期过敏原致敏后更明显的高反应性的中介。其次，将在兔和小鼠身上确定正常发生的、由生命早期对过敏原致敏产生的胆碱能功能改变的机制。这些研究将确定早期损伤是否会增加气道内含有P物质（SP）的神经和/或SP受体的数量，并确定早期致敏是否会改变毒蕈碱自身受体的功能和/或表达，该受体通常会下调胆碱能神经中乙酰胆碱的释放。第三，新生儿过敏原致敏过程中神经介导的松弛反应丧失的机制将在家兔中进行研究。气道平滑肌功能的生化控制可能会导致这种松弛途径的丧失，这将是一个重点。这些哺乳动物物种气道发育生物学的研究允许对可能与婴幼儿发生的事件相关的神经免疫机制进行定义。

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.