NF-KB ACTIVATION BY BRONCHIOLAR EPITHELIUM IN ASTHMA

本研究的假设是，在小鼠过敏性哮喘模型中观察到的气道上皮细胞中转录因子核因子-κ B（NF-κ B）的激活在病理表型的发展中起着主动作用。 该假设将在3个具体目标中进行检验。 具体目标1是确定过敏原激发后细支气管上皮中NF-κ B活化的时间过程以及与炎症诱导和肺功能改变的相关性。 具体目标2将是检测免疫接种和过敏原激发后细支气管上皮细胞中NF-κ B调节基因RANTES、嗜酸性粒细胞趋化因子和IL-6的mRNA和蛋白表达。 最后，具体目标3将确定使用仅在细支气管上皮中表达IkappaB α超阻遏物的转基因小鼠抑制NF-κ B活化是否能预防与哮喘相关的炎症反应和肺生理学改变的产生。这些研究的结果将证实细支气管上皮细胞中NF-κ B信号级联在过敏性哮喘发生中的重要性。 这些知识将为设计更有效的治疗过敏性哮喘和其他炎症性肺病的方法提供机制基础。

The hypothesis to be investigated in this proposal is that activation of the transcription factor, Nuclear Factor-kappaB (NF-kappaB), in epithelial cells of conducting airways plays an initiative role in the development of the pathologic phenotype observed in a murine model of allergic asthma. The hypothesis will be tested in 3 specific aims. Specific Aim number 1 will be to determine the time-course of NF-kappaB activation in bronchiolar epithelium following allergen challenge and correlation with induction of inflammation and alterations in pulmonary function. Specific Aim number 2 will be to examine the mRNA and protein expression of the NF-kappaB regulated genes RANTES, eotaxin, and IL-6 in bronchiolar epithelial cells following immunization and challenge with allergen. Finally, Specific Aim number 3 will be to determine whether inhibition of NF-kappaB activation, using a transgenic mouse expressing a IkappaBalpha superrepressor exclusively in bronchiolar epithelium, prevents the generation of inflammatory responses and alterations in pulmonary physiology associated with asthma. Results of these studies will demonstrate the importance of NF- kappaB signaling cascades in bronchiolar epithelium, in development of allergic asthma. This knowledge will provide the mechanistic foundation for the design of more effective therapies for allergic asthma and other inflammatory lung diseases.