Airway Biology of Acute Environmental Asthma in Humans

项目3，“人类急性环境性哮喘的气道生物学”将研究 环境内毒素对哮喘急性发作的影响流行病学研究表明， 环境颗粒物（PM）和内毒素（PM的一种成分）与增加的 哮喘急性发作和喘息的发生。发表了我们小组和其他人的报告 证明内毒素在气道中诱导先天性反应，其特征在于 单核细胞/巨噬细胞生物学和气道嗜中性粒细胞的流入。我们还表明，这些 应答与气道巨噬细胞上的CD 14表达密切相关。低水平内毒素预充 从而增强过敏性哮喘患者对过敏原反应，并导致全身 假设污染物通过先天免疫机制启动气道， 额外的污染物或过敏原是引发环境性哮喘的中心过程。 虽然环境内毒素诱导哮喘恶化是明确的，但仍存在显著差距 关于调节这种环境刺激物引起的炎症的机制的知识。 我们小组最近的初步数据表明，IL-1 β是内毒素诱导的一种重要的调节剂， 气道中的事件。最近发现的CATERPILLER免疫家族成员 调节蛋白在调节IL-1 β诱导的炎症中起重要作用，我们假设 CATERPILLER基因在调节污染物诱导的哮喘中是重要的。病原体信号 相关的分子模式实体（如内毒素）激活cryopyrin和NALP 1，并诱导 负调节蛋白Monarch-1的丢失。除了被PAMP激活外，cryopyrin还被 由内源性配体如ATP（其由发炎/损伤的气道细胞释放）激活， 连接到P2 X7受体。项目1和2关注这些分子在介导 气道对LPS的反应，在过敏原致敏和naTve之间观察到的这些反应的差异 小鼠，以及内毒素对过敏原应答的启动作用。该项目的目标是 检测过敏原和内毒素诱导的炎症对CATERPILLAR表达的影响 调节因子、P2 X7受体和其他分子，其通过气道增强先天性和免疫应答 单核细胞、粒细胞和上皮细胞在过敏性哮喘中的作用， 过敏性炎症，以及抗炎治疗对这些过程的影响。

Project 3, "Airway Biology of Acute Environmental Asthma in Humans" will examine the effect of environmental endotoxin on acute exacerbation of asthma. Epidemiological studies have shown that environmental particulate matter (PM) and endotoxin (a component of PM) are associated with increased occurrences of asthma exacerbation and wheeze. Published reports from our group and others demonstrate that endotoxin induce an innate response in the airway characterized by changes in monocyte/macrophage biology and influx of airway neutrophils. We have also shown that these responses correlate well to expression of CD14 on airway macrophages. Low levels of endotoxin prime the airway such that response of allergic asthmatics to allergens is enhanced, and lead to the general hypothesis that priming of the airway by pollutants via innate immune mechanisms to respond to additional pollutants or allergens is a central process by which environmental asthma is initiated. Though it is clear that environmental endotoxin induces asthma exacerbation, there is a significant gap in knowledge regarding the mechanisms which modulate inflammation due to this environmental irritant. Recent preliminary data from our group suggest that IL-1 (3 is an important modulator of endotoxin induced events in the airway. The recently discovered members of the CATERPILLER family of immune regulatory proteins play an important role in regulating IL-1p induced inflammation and we hypothesize that CATERPILLER genes are important in regulating pollutant induced asthma. Signals from pathogen associated molecular patterns entities (such as endotoxin) activate cryopyrin and NALP1, and induce the loss of the negative regulator protein monarch-1. In addition to being activated by PAMPs, cryopyrin is activated by endogenous ligands such as ATP (which is released by inflamed/injured airway cells) after ligation to the P2X7 receptor. Projects 1 and 2 focus on the role that these molecules have in mediating airway responses to LPS, differences in these responses observed between allergen sensitized and naTve mice, and the priming effect of endotoxin on response to allergen. This aims of this project will be to examine the effect of allergen and endotoxin-induced inflammation on expression of CATERPILLAR regulators, P2X7 receptors and other molecules which enhance innate and immune response by airway monocytes, granulocytes and epithelial cells in allergic asthmatics, the modification of response to LPS by allergic inflammation, and the effect of anti-inflammatory therapy on these processes.