ROLE OF INNATE IMMUNITY IN OZONE-INDUCED ASTHMA EXACERBATIONS

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 过敏性哮喘是一种复杂的呼吸道炎症性疾病，以气道高反应性(AHR)、嗜酸性粒细胞和淋巴细胞向肺内浸润、血清IgE升高、粘液高分泌和气道重塑为特征。臭氧导致哮喘加重的细胞和分子机制还不是很清楚。几个实验室的最新发现表明，产生IL-17的T细胞介导了小鼠暴露在臭氧或其他环境污染物中后的AHR和肺部炎症。IL-17在肺中的作用是多方面的，包括激发中性粒细胞的募集，以及通过上皮细胞和聚合免疫球蛋白受体介导的IgA进入呼吸道诱导抗菌肽。CD4Th17细胞是这种细胞因子的主要来源，但T细胞也被证明是天然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驻留在肺内的产生IL-17的T细胞增加。这种T细胞表达E 7整合素，并与呼吸道上皮细胞密切相关。我们推测，在过敏性呼吸道炎症期间，气道上皮细胞中会产生大量产生IL-17的T细胞，这将增强呼吸道的天然免疫，并导致对环境氧化剂损害的过度反应，典型的表现为慢性肺部炎症和AHR增加。我们建议解决以下目标：(I)表征与呼吸道相关的产生IL-17的T细胞在过敏性气道炎症中的反应，以及细胞因子在推动它们在肺中扩张的作用。(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.