Through the interplay of multiple cells, cytokines, and inflammatory molecules, allergic inflammation can become chronic and associated with significant morbidity. Kinins are pluripotent inflammatory mediators that are well recognized to play an important role in airway inflammation. Bradykinin (BK) has been shown to be critical for the development of both the late phase asthmatic response as well as delayed bronchial hyperresponsiveness following antigen challenge. The role of des-Arg-BK in airway inflammation has not been elucidated however recent evidence from our laboratories suggest that it may also be an important contributor to chronic asthmatic inflammation. The precise mechanism(s) by which kinins contribute to airway inflammation remains to be fully elucidated. We recently demonstrated that BK, acting through B2 BK receptors, potently activates the transcription factor NF-kB thereby stimulating cytokine synthesis. We have now demonstrated that BK also activates NF-kB in epithelial cells. Additionally, we have shown that des-Arg-BK, acting through B1 BK receptors, activates the transcription factor AP-1, and that BK can upregulate B1 BK receptors. The major hypothesis of this proposal is that kinins promote the development of chronic airway inflammation through their ability to activate transcription factors in airway cells leading to: increased synthesis of cytokines, chemokines and adhesion molecules; and facilitating the recruitment of additional inflammatory effector cells. These transcriptional effects of kinins, rather than their classic effects on smooth muscle tone and vascular permeability, may thus help provide the critical signals, bridging the progression of acute allergic reactions into chronic airway inflammation. We propose to 1) assess the role of BK in mediating airway epithelial cell synthesis of cytokines both in vitro and in vivo, utilizing both transformed and primary human airway epithelial cells as well as in vivo nasal challenges; and 2) analyze the molecular mechanisms regulating expression and functional coupling of B1 BK receptor expression in airway fibroblasts and epithelial cells, including analyzing the G protein-associated signaling pathways utilized by B1 BK receptors in human airway cells. This Project will have multiple interactions with the other Projects in the Program, including: sharing of a murine model of in vivo airway inflammation (Project 3); analysis of B1 BK receptor expression in T cell subsets (Project 1); assessment of kinin-mediated phosphorylation of actin-binding proteins (Project 2); and use of the FACS (FACS Core) and biostatistician (Administrative Core).
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