Airway Biology of Acute Environmental Asthma in Humans

项目3，“人类急性环境性哮喘的呼吸道生物学”将研究 环境内毒素对哮喘急性加重期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 哮喘加重和喘息的发生。我们小组和其他人发布的报告 证明内毒素在呼吸道中诱导先天反应，其特征是改变 单核/巨噬细胞生物学与呼吸道中性粒细胞的流入。我们还表明，这些 应答与呼吸道巨噬细胞表面CD14的表达密切相关。低水平的内毒素原 呼吸道使过敏性哮喘患者对变应原的反应增强，并导致一般 假设污染物通过先天免疫机制启动呼吸道以应对 额外的污染物或过敏原是引发环境性哮喘的一个中心过程。 尽管环境内毒素导致哮喘加重是显而易见的，但两者之间存在着显著的差距。 关于这种环境刺激物引起的炎症的调节机制的知识。 本课题组最近的初步数据表明，IL-1(3)是内毒素诱导的重要调节剂 呼吸道内发生的事件。最近发现的卡特彼勒免疫家族成员 调节蛋白在调节IL-1p诱导的炎症中起重要作用，我们假设 毛虫基因在控制污染物引起的哮喘中起着重要作用。来自病原体的信号 相关的分子模式实体(如内毒素)激活低温比林和NALP1，并诱导 负性调节蛋白MUNARCH-1的缺失。除了被PAMP激活外，低温比林还被 由内源性配体激活，如ATP(由炎症/损伤的呼吸道细胞释放) 与P2X7受体连接。项目1和2的重点是这些分子在调节 过敏原致敏和NATve致敏的呼吸道对内毒素的反应的差异 小鼠，以及内毒素对变应原反应的启动作用。该项目的目标将是 过敏原和内毒素诱导的炎症对毛虫表达的影响 调节剂、P2X7受体和其他通过呼吸道增强先天免疫反应的分子 过敏性哮喘患者单核细胞、粒细胞和上皮细胞对内毒素反应的影响 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.