KININS, SIGNALING AND ASTHMA

激肽、信号传导和哮喘

• 批准号: 6340711
• 负责人: Bruce L. Zuraw
• 金额: $ 12.57万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2001-10-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6340711
• 关键词: G protein; biological signal transduction; bradykinin; cooperative study; cytokine; inflammation; kinins; neuropeptide receptor; nuclear factor kappa beta; receptor coupling; receptor expression; respiratory epithelium; respiratory hypersensitivity; tissue /cell culture

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).

通过多个细胞、细胞因子和 炎症分子，过敏性炎症可成为慢性 并与显著的发病率相关。Kinins是 公认的多效炎性介质 在呼吸道炎症中起重要作用。缓激肽(BK) 已经被证明对两个国家的发展都至关重要 晚期哮喘反应和延迟的支气管反应 抗原攻击后的高反应性。的作用 DES-Arg-BK在呼吸道炎症中的作用尚未阐明 然而，最近来自我们实验室的证据表明， 可能也是慢性哮喘的一个重要因素 发炎。激动素的精确机制(S) 对呼吸道炎症的贡献仍有待充分 已澄清。 我们最近演示了BK，通过B2BK表演 受体，有效地激活转录因子核因子-kB 从而刺激细胞因子的合成。我们现在有了 证明BK还能激活上皮细胞中的核因子-kB。 此外，我们已经证明了Des-Arg-BK，通过B1起作用 BK受体，激活转录因子AP-1，并且 BK可上调B1BK受体。这其中的主要假设 有观点认为激肽可促进慢性阻塞性肺疾病的发展 通过它们的激活能力引起的呼吸道炎症 呼吸道细胞中的转录因子导致：增加 细胞因子、趋化因子和黏附分子的合成； 促进招募更多的炎症效应因子 细胞。激肽的这些转录效应，而不是 它们对平滑肌张力和血管的经典作用 渗透率，因此可以帮助提供关键信号， 将急性过敏反应的进展连接到 慢性呼吸道炎症。 我们建议1)评估BK在调节呼吸道中的作用 上皮细胞在体外和体外对细胞因子的合成 活体，利用转化的和原始的人类呼吸道 上皮细胞和活体鼻腔挑战；以及2) 分析调控基因表达和表达的分子机制 B1BK受体在呼吸道表达的功能偶联 成纤维细胞和上皮细胞，包括分析G B1BK利用的蛋白相关信号通路 人类呼吸道细胞中的受体。该项目将拥有 与计划中的其他项目进行多次互动， 包括：分享体内呼吸道的小鼠模型 炎症(项目3)：B1BK受体表达分析 在T细胞亚群中(项目1)；激肽介导的评估 肌动蛋白结合蛋白的磷酸化(项目2)；和用途 生物统计师(行政管理) 核心)。