Neuro-Immune Interactions in Developing Airways

气道发育中的神经免疫相互作用

• 批准号: 6607687
• 负责人: GARY L LARSEN
• 金额: $ 34.11万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-04 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6607687
• 关键词: T lymphocyte; acetylcholine; age difference; allergens; asthma; bronchomotion; cytokine; developmental immunology; genetic susceptibility; inflammation; laboratory mouse; laboratory rabbit; leukocyte activation /transformation; lung injury; methacholine; neprilysin; neuroimmunomodulation; neuropeptide receptor; pathologic process; phosphodiesterases; respiratory function; respiratory infections; smooth muscle; substance P

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.

哮喘的发病率在生命的最初几年最高。 在此期间，免疫功能和气道控制机制正在发生发育变化。气道疾病模型的研究表明，当生命早期发生免疫/炎症事件时，气道控制的改变可能是明显且持久的。 该提案的目标是描述发育中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部内的炎症反应导致气道内神经元件的重塑。 此外，当损伤发生在遗传易感宿主的生命早期时，这些变化最为显着。 然而，当损伤发生在免疫成熟过程中的关键窗口期间时，对易感宿主的这种需求可能会被克服。 研究将在体内和体外进行，重点是无法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来实现。 首先，将解决当 BALB/c 小鼠在较年轻时对过敏原敏感时气道反应性更大增强的机制。 不同年龄产生的免疫/炎症反应将被定义并与作为年龄函数的T淋巴细胞亚群/细胞因子表达相关。 T 细胞亚群及其产物的消耗和重建将用于定义早期过敏原致敏后注意到的更显着的高反应性的介导。其次，将在兔子和小鼠中定义负责正常发生并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通常下调乙酰胆碱释放的毒蕈碱自身受体的功能和/或表达。胆碱能神经。第三，将在兔子中研究导致新生儿过敏原致敏发生的神经介导的松弛反应丧失的机制。 气道平滑肌功能的生化控制可能是导致这种松弛途径丧失的原因，这将成为焦点。 这些对哺乳动物物种发育气道生物学的研究可以定义可能与婴儿和幼儿中发生的事件相关的神经免疫机制。