Prenatal diesel exposure and adult onset asthma

描述（由申请人提供）：哮喘一直被认为是一种复杂的遗传疾病，受一生中经历的环境触发因素的影响。然而，最近的证据表明，哮喘的发作可能受到子宫内环境暴露的调节。暴露于柴油废气颗粒（DEP）与肺形成减少有关。此外，较高的DEP暴露与花粉敏感的风险增加有关，并且与Th2细胞因子的上调有关，Th2细胞因子被认为是过敏性哮喘的基础。但是，尽管越来越多的证据表明，产前暴露于过敏原与随后发作的哮喘相关表型有关，但产前暴露于DEP对后来发作的哮喘的调节作用尚未阐明。此外，其机制，包括产前暴露于DEP对肺发育和差异基因表达的影响，尚未研究。我们假设产前柴油暴露会增加成人发作哮喘的风险。我们的策略是研究产前DEP暴露对哮喘的影响，方法是采用可靠的小鼠模型进行抗原特异性致敏，并利用它们研究与成人哮喘相关的表型，包括IgE产生增强、Th2谱系的承诺、气道高反应性和气道重塑。我们预测，产前DEP暴露将导致IgE类转换和Th2分化增加，从而增加成人发病哮喘的风险。我们还预测，子宫内暴露于DEP后检测到的肺发育变化和/或差异基因表达将与成人哮喘有关。我们期望通过对子宫内环境刺激的免疫和遗传反应的重要性及其对后期疾病的影响的研究，可以更好地了解环境污染物在哮喘发病机制中的作用，并最终制定更好的预防策略。具体来说，我们提出：目的1：确定产前DEP暴露是否会增加后代的IgE产生和Th2谱系的承诺。目的2：确定产前DEP暴露是否与发育中的肺上皮细胞分化改变有关。目的3：确定产前DEP暴露是否与成年小鼠气道高反应性或气道重塑增加有关。目的4：确定a)子宫内柴油暴露后的差异基因表达，以及b)产前柴油暴露后的差异基因表达是否与成人哮喘有关。

DESCRIPTION (provided by applicant): Asthma has long been considered a complex genetic disease that is subject to environmental triggers experienced over a lifetime. Yet more recent evidence suggests that the onset of asthma may be modulated by intra-uterine environmental exposures. Exposure to diesel exhaust particles (DEP) has been associated with decreased lung formation. In addition, higher DEP exposure has been associated with a greater risk of becoming sensitized to pollen, and with up regulation of Th2 cytokines thought to underly atopy or allergic asthma. But despite growing evidence implicating prenatal allergen exposure to the subsequent onset of asthma-related phenotypes, the modulatory role of prenatal exposure to DEP to the later onset of asthma has not been elucidated. Furthermore, the mechanisms, including the impact of prenatal DEP exposure on lung development and differential gene expression, have not been studied. We hypothesize that prenatal diesel exposure can increase the risk for adult-onset asthma. Our strategy will be to study the effects of prenatal DEP exposure to asthma by employing reliable mouse models for antigen-specific sensitization and using them to study phenotypes associated with adult asthma, including augmented IgE production, commitment to the Th2 lineage, airway hyperreactivity, and airway remodeling. We predict that prenatal DEP exposure will lead to increased IgE class switching and Th2 differentiation, thereby promoting the risk for adult-onset asthma. We also predict that lung developmental changes and/or differential gene expression detected following in utero exposure to DEP will be associated with adult asthma. We anticipate that a study of the importance of immunologic and genetic responses to intra-uterine environmental stimuli, and their impacts on later disease, could lead to a better understanding of the role of environmental pollutants to asthma pathogenesis, and ultimately better strategies for prevention. Specifically, we propose to: Aim 1: Determine whether prenatal DEP exposure augments IgE production and commitment to Th2 lineage in the offspring. Aim 2: Determine whether prenatal DEP exposure is associated with altered epithelial cell differentiation in the developing lung. Aim 3: Determine whether prenatal DEP exposure is associated with increased airway hyper reactivity or airway remodeling in adult mice. Aim 4: Determine a) the differential gene expression following in utero diesel exposure, and b) whether differential gene expression following prenatal diesel exposure is associated with adult asthma.