ROLE OF INNATE IMMUNITY IN OZONE-INDUCED ASTHMA EXACERBATIONS

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 变应性哮喘是一种复杂的气道炎症性疾病，以气道高反应性（AHR）、嗜酸性粒细胞和淋巴细胞浸润、血清IgE升高、粘液高分泌和气道重塑为特征。臭氧引起哮喘急性发作的细胞和分子机制还不清楚。最近几个实验室的研究结果表明，在小鼠暴露于臭氧或其他环境污染物后，产生IL-17的T细胞介导AHR和肺部炎症。IL-17在肺中的作用是多方面的，包括引起嗜中性粒细胞的募集，并通过上皮细胞诱导抗微生物肽和多聚免疫球蛋白受体介导的伊加递送到气道中。CD 4 + Th 17细胞是这种细胞因子的主要来源，但也显示出T细胞是先天性IL-17的有效来源。我们的初步实验表明，过敏性肺部炎症导致肺部产生IL-17的T细胞增加。这种T细胞表达E 7整联蛋白，并与气道上皮密切相关。我们假设，在过敏性气道炎症过程中，气道上皮细胞中会产生大量的E 7+ IL-17 + T细胞，这将增强气道先天免疫，并导致对环境氧化剂损伤的过度反应，其典型表现为慢性肺部炎症和AHR增加。我们提出了以下目标：（i）描述过敏性气道炎症期间气道相关IL-17产生的T细胞的反应以及细胞因子在驱动其在肺中扩增中的作用。(ii)研究产生IL-17的T细胞在臭氧诱导的AHR和过敏性肺部炎症加重中的作用，并开发限制慢性肺部炎症的新方法。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Allergic asthma is a complex airway inflammatory disorder, characterized by airway hyperreactivity (AHR), eosinophil and lymphocyte infiltration into the lungs, elevated serum IgE, increased mucus hypersecretion and airway remodeling. The cellular and molecular mechanisms underlying asthma exacerbations induced by ozone are not well understood. Recent findings by several laboratories have shown that IL-17-producing T cells mediate AHR and lung inflammation following exposure of mice to ozone or other environmental pollutants. The actions of IL-17 in the lungs are multifaceted and include eliciting the recruitment of neutrophils, and inducing anti-microbial peptides by epithelial cells and polymeric immunoglobulin receptor-mediated delivery of IgA into the airways. The CD4+ ¿¿ Th17 cells are a major source of this cytokine, but also ¿¿ T cells have been shown to be potent source of innate IL-17. Our preliminary experiments demonstrate that allergic lung inflammation results in an increase in IL-17-producing ¿¿ T cells residing in the lung. Such ¿¿ T cells express the ¿E¿7 integrin and are closely associated with the airway epithelium. We hypothesize that during allergic airway inflammation will result in large numbers of ¿E¿7+ IL-17-producing ¿¿ T cells in the airway epithelium that will augment airway innate immunity and result in exaggerated responses to environmental oxidant insults typified by chronic lung inflammation and increased AHR. We propose to address the following aims: (i) To characterize the response of airway-associated IL-17-producing ¿¿ T cells during allergic airway inflammation and the role of cytokines in driving their expansion in the lung. (ii) To examine the contribution of IL-17-producing ¿¿ T cells in ozone-induced AHR and exacerbations of allergic lung inflammation and develop novel approaches in limiting chronic lung inflammation.