Prenatal control of offspring airway responsiveness

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We have recently shown that there is a fundamental difference in airway physiology between wildtype mice born to wildtype mothers and wildtype mice born to IL5 overexpressing mothers or housedust mite (HDM) sensitized mothers. The airways of adult wildtype offspring of these mothers are much more responsive, an effect that requires fetal eosinophilia that develops as the result of maternal IL5 crossing the placenta. Subsequent sensitization and challenge with housedust mite yields much more severe bronchoconstriction. The central hypothesis of this project is that high circulating IL5 during pregnancy induces fetal eosinophilia, and that this causes permanent changes in airway innervation that increase bronchoconstriction. In this project, we propose to determine the mechanisms of airway hyperreactivity in these WT offspring of IL5 transgenic mothers. We will characterize changes in airway nerve structure, transmitters, and receptor expression. We propose three specific aims: SPECIFIC AIM #1: Test the effects of maternal IL5tg and maternal HDM challenge on reflex bronchoconstriction, parasympathetic nerve function, and smooth muscle function. We will determine the role of maternal fetal transfer of IL5 in the maternal HDM challenge model, and test the role of maternal and fetal eosinophilia in these effects. We will also dissect the mechanisms of severe, lethal bronchoconstriction and potentiated airway inflammation when these adult offspring are antigen challenged. SPECIFIC AIM #2: Test whether exposure to IL5 in utero alters the architecture or neurotransmitter content of sensory and parasympathetic nerves. We will use our novel imaging method to determine epithelial and smooth muscle innervation, and to quantify changes in neurotransmitter expression in sensory and parasympathetic nerves. SPECIFIC AIM #3: To determine the role of airway epithelial neurotrophins in 1) heightened response to antigen challenge, 2) severe airway hyperresponsiveness, and 3) maintenance of airway nerve remodeling in adult offspring of IL5tg mothers and in adult offspring of HDM sensitized and challenged mothers. We will extend our preliminary studies of neurotrophin expression to include the different mouse models and treatments in Aim #1, and determine the roles of neurotrophins that are elevated by blocking with antibodies and treating animals with receptor antagonists.