Inhaled environmental particles, pregnancy and neonatal allergy

描述(由申请人提供) 问题和试点数据：孕期环境暴露可能会影响发育中儿童未来的健康，但具体机制尚不清楚。试点数据显示，怀孕期间暴露在柴油废气颗粒物中的母鼠的后代比正常母亲的幼鼠更容易过敏。值得注意的是，这种影响也是由控制“惰性”二氧化钛颗粒引起的。此外，“惰性”颗粒实际上对怀孕的小鼠是致病/促炎的(而在非怀孕的对照组中造成的影响很小)。因此，怀孕导致肺部对环境因素的反应发生了迄今为止尚未被认识到的变化，从而提出了中心假说：与怀孕相关的激素改变了局部肺对吸入环境颗粒物的先天免疫反应，导致全身细胞因子调节发育中的后代免疫，使其对过敏更敏感。 具体目的1：描述妊娠小鼠对环境颗粒物的局部肺和全身反应，检验在BAL分析、血清和肺基因表达谱多重细胞因子分析中增强的前Th2反应的预测性。 具体目的2：研究妊娠激素对肺泡巨噬细胞(AM)对颗粒反应的影响，在体外和体内验证孕激素和雌激素促进前Th2 AM对颗粒反应的预测。具体目标3：通过中和抗体和细胞因子治疗策略，测试Th2细胞因子在妊娠期间颗粒介导的效应中的因果作用。 意义：严格的导师制(目标1)将为候选人过渡到独立(目标2和3)做好准备，并继续发展他在教职员工层面的环境疾病研究生涯。这项研究将为哮喘早期生命起源的基本问题和环境因子如何调节子宫效应的应用问题提供新的见解。

DESCRIPTION (provided by applicant) Problem and Pilot Data: Environmental exposures during pregnancy can influence the future health of the developing child, but specific mechanisms are unknown. Pilot data show that offspring of mother mice exposed during pregnancy to diesel exhaust particles are more susceptible to allergy than babies of normal mothers. Remarkably, this effect is also caused by control, "inert" titanium dioxide particles. Moreover, '"inert" particles are actually pathogenic/pro-inflammatory in pregnant mice (while causing minimal effects in non pregnant controls). Hence, pregnancy causes a heretofore unrecognized change in lung responses to environmental agents, prompting the central hypothesis: pregnancy-related hormones alter local lung innate immune responses to inhaled environmental particles, leading to systemic cytokine modulation of developing offspring immunity to a state of greater susceptibility to allergy. Specific aim 1: To characterize the local pulmonary and systemic response of pregnant mice to environmental particles, testing the prediction of enhanced pro-Th2 responses in BAL analysis, multiplex cytokine assays of serum and lung gene expression profiling. Specific aim 2: To characterize effects of pregnancy hormones on the alveolar macrophage (AM) response to particles, testing the prediction that progesterone and estrogen promote pro-Th2 AM responses to particles in vitro and in vivo. Specific aim 3: To test the causal role of Th2 cytokines in particle-mediated effects during pregnancy by neutralizing antibody and cytokine treatment strategies. Significance: Rigorous mentorship (aim 1) will prepare the candidate for transition to independence (Aims 2 and 3) and continue developing his research career in environmental disease at a faculty level. This research will provide novel insights into the basic question of early life origins of asthma and the applied question of how environmental agents mediate in utero effects.