Prenatal control of offspring airway responsiveness

我们最近发现野生型小鼠在呼吸道生理学上有根本的不同。 野生型母亲和野生型小鼠出生的IL5过表达的母亲或家尘螨(HDM) 敏感的母亲。这些母亲的成年野生型后代的呼吸道反应要快得多， 需要胎儿嗜酸性粒细胞增多症的影响，这是母体IL5穿过胎盘的结果。 随后用尘螨致敏和激发会产生更严重的支气管收缩。 该项目的中心假设是妊娠期间循环中的高IL5诱导胎儿 嗜酸性粒细胞增多症，这会导致呼吸道神经支配的永久性变化，增加 支气管收缩。在这个项目中，我们建议确定呼吸道高反应性的机制。 这些白介素5转基因母亲的WT后代。我们将描述呼吸道神经结构的变化， 递质和受体的表达。我们提出三个具体目标： 具体目标1：测试母体IL5tg和母体HDM挑战对反射的影响 支气管收缩、副交感神经功能和平滑肌功能。我们将确定 母体胎儿移植IL5在母体HDM挑战模型中的作用，并测试母体和 胎儿嗜酸性粒细胞增多症的这些影响。我们还将剖析严重的、致命性的支气管收缩的机制 当这些成年后代受到抗原攻击时，会加剧呼吸道炎症。 具体目标2：测试宫内暴露于IL5是否会改变脑组织结构或神经递质含量 感觉神经和副交感神经。我们将使用我们的新成像方法来确定上皮和 平滑肌神经支配，并量化神经递质在感觉和 副交感神经。 特定目的#3：确定呼吸道上皮神经营养因子在1)增强对 抗原攻击，2)严重的气道高反应性，以及3)维持气道神经重建。 IL5tg母亲的成年后代和HDM的成年后代致敏和挑战母亲。我们会 扩展我们对神经营养因子表达的初步研究，以包括不同的小鼠模型和 目标1中的治疗，并确定通过抗体阻断而升高的神经营养因子的作用 用受体拮抗剂治疗动物。

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.