KININS, SIGNALING AND ASTHMA

通过多种细胞、细胞因子和 炎症分子，过敏性炎症可成为慢性 并且与显著的发病率相关。 激肽是 多能性炎症介质被公认为 在气道炎症中起重要作用。 缓激肽（BK） 已被证明是至关重要的发展， 晚期哮喘反应以及延迟的支气管 抗原攻击后的高反应性。 的作用 des-Arg-BK在气道炎症中的作用尚未阐明 然而，我们实验室最近的证据表明， 也可能是慢性哮喘的重要原因 炎症 激肽的精确机制 有助于气道炎症仍然是充分的 阐明。 我们最近证明BK通过B2 BK 受体，有效地激活转录因子NF-κ B 从而刺激细胞因子合成。 我们现在已经 表明BK也激活上皮细胞中的NF-kB。 此外，我们已经表明，des-Arg-BK，通过B1 BK受体，激活转录因子AP-1， BK可上调B1 BK受体。 主要的假设是 建议是激肽促进慢性 气道炎症通过它们激活 气道细胞中的转录因子导致：增加 细胞因子、趋化因子和粘附分子的合成;以及 促进额外的炎症效应物的募集 细胞 这些激肽的转录作用，而不是 它们对平滑肌张力和血管张力的经典作用 渗透性，因此可以帮助提供关键信号， 将急性过敏反应的进展 慢性气道炎症 我们建议：1）评估BK在介导气道 上皮细胞合成细胞因子的体外和体内研究 体内，利用转化的和原代人气道 上皮细胞以及体内鼻攻击;和2） 分析调控表达的分子机制， 气道B1-BK受体表达的功能偶联 成纤维细胞和上皮细胞，包括分析G B1 BK利用的蛋白相关信号通路 人体呼吸道细胞中的受体。 该项目将有 与计划中其他项目的多次互动， 包括：共享体内气道的小鼠模型 炎症（项目3）; B1 BK受体表达分析 T细胞亚群（项目1）;激肽介导的 肌动蛋白结合蛋白的磷酸化（项目2）; 和生物统计学家（行政 核心）。

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).