NF-KB ACTIVATION BY BRONCHIOLAR EPITHELIUM IN ASTHMA

本研究拟研究的假设是，传导气道上皮细胞中转录因子核因子- kappab （NF-kappaB）的激活在小鼠变应性哮喘模型中观察到的病理表型的发展中起主动作用。该假设将在三个具体目标中进行检验。具体目标1将是确定在过敏原攻击后细支气管上皮中NF-kappaB激活的时间过程及其与炎症诱导和肺功能改变的相关性。特异性目标2将检测NF-kappaB调控基因RANTES、eotaxin和IL-6在免疫和过敏原刺激后细支气管上皮细胞中的mRNA和蛋白表达。最后，特异性目标3将是确定是否使用在细支气管上皮中表达IkappaBalpha超抑制因子的转基因小鼠抑制NF-kappaB激活，可以防止炎症反应的产生和哮喘相关的肺生理改变。这些研究结果将证明NF- kappaB信号级联在支气管上皮变应性哮喘发展中的重要性。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部疾病的机制基础。

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.