NF-KB ACTIVATION BY BRONCHIOLAR EPITHELIUM IN ASTHMA

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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.