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.
