BETA-ADRENERGIC RECEPTOR REGULATION IN AIRWAY EPITHELIUM

气道上皮中 β-肾上腺素能受体的调节

• 批准号: 3365059
• 负责人: Jeffrey L Benovic
• 金额: $ 26.07万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-09-30 至 1991-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3365059
• 关键词: Ambrosia; G protein; active immunization; adenylate cyclase; affinity labeling; airborne allergen; asthma; beta adrenergic agent; beta adrenergic receptor; beta antiadrenergic agent; biological signal transduction; bradykinin; cyclic AMP; genetic transcription; human tissue; inflammation; laboratory rabbit; messenger RNA; natural gene amplification; nucleic acid sequence; phosphorylation; polymerase chain reaction; prostaglandin E; receptor coupling; receptor expression; receptor sensitivity; respiratory airflow disorder; respiratory epithelium; substance P

Stimulation of beta-adrenergic receptors (beta-AR) on the tracheobronchial epithelium elicits a variety of cellular responses which affect the defense of the respiratory tract and which may alter the intensity of the inflammatory response in the airway. Beta-adrenergic agonists acting on the tracheobronchial epithelium affect salt and water exchange across the airway wall, mucus secretion and mucociliary clearance, and release of bronchoactive substances. Studies in a variety of cellular systems have demonstrated that the response to beta-adrenergic agonists is dynamic and may be altered by such agents as beta-agonists and phorbol esters. Furthermore, alterations in adrenergic responsiveness may play an important role in the clinical manifestations and treatment of airway diseases such as asthma. Surprisingly, little is known about the beta-AR receptors on tracheobronchial epithelial cells in man. Moreover, the regulation of the beta-AR receptor-coupled adenylyl cyclase system by beta-agonists and inflammatory mediators present in the airway (e.g. bradykinin, substance P, prostaglandin E2) remains undefined in these cells. This gap in our knowledge is of obvious C3 importance to our understanding of the pathogenesis of airway disease and its response to therapy. The objectives of this proposal are to characterize the beta-AR-coupled adenylyl cyclase system in isolated tracheobronchial epithelial cells obtained from rabbits and humans. The beta-AR will initially be characterized with regard to density, subtype, coupling to the G protein (Gs) and to adenylyl cyclase . The subtype of the beta-AR in the human epithelial cells will be determined by the polymerase chain reaction. The effects of agents which raise intracellular cAMP levels (e.g. beta-agonists, forskolin, phosphodiesterase inhibitors) on the responsiveness of the adenylyl cyclase system will be assessed. The potential mechanisms involved in any altered regulation will be elucidated by determining receptor distribution, phosphorylation state and mRNA levels. Similar studies will be used to characterize the effects of phorbol esters and inflammatory mediators (e.g. bradykinin, substance P, prostaglandin E2) on the beta-AR-coupled adenylyl cyclase system in isolated epithelial cells. Finally, the effects of aerosolized allergens on this system will be assessed in ragweed-sensitized rabbits and in stable human asthmatics. These studies should help elucidate the mechanisms regulating the beta-AR-coupled adenylyl cyclase system in normal epithelial cells and in cells isolated from inflamed airways.

刺激气管支气管上的β-肾上腺素能受体（β-AR） 上皮细胞激发多种细胞反应， 这可能会改变呼吸道的强度， 气道炎症反应。β-肾上腺素能激动剂作用于 气管支气管上皮影响跨支气管的盐和水交换， 气道壁、粘液分泌和粘膜纤毛清除，以及 支气管活性物质。在各种细胞系统中的研究 表明对β-肾上腺素能激动剂的反应是动态的， 可以被诸如β-激动剂和佛波酯的药剂改变。 此外，肾上腺素能反应性的改变可能在 在气道疾病的临床表现和治疗中的作用， 哮喘。令人惊讶的是，关于β-AR受体的知之甚少。 气管支气管上皮细胞在人。此外，调节的 通过β-激动剂的β-AR受体偶联腺苷酸环化酶系统， 存在于气道中的炎症介质（例如缓激肽，P物质， 前列腺素E2）在这些细胞中仍然不确定。我们之间的差距 知识对于我们理解C3的重要性是显而易见的。 气道疾病的发病机制及其对治疗的反应。 本提案的目的是表征β-AR-耦合 离体气管支气管上皮细胞腺苷酸环化酶系统 从兔子和人身上获得。Beta-AR最初将 根据密度、亚型、G蛋白偶联 (Gs)和腺苷酸环化酶。人类β-AR的亚型 上皮细胞将通过聚合酶链反应来确定。的 提高细胞内cAMP水平的试剂（例如， β-激动剂，毛喉素，磷酸二酯酶抑制剂） 将评估腺苷酸环化酶系统的反应性。的 将阐明任何改变调节的潜在机制 通过测定受体分布、磷酸化状态和mRNA 程度.类似的研究将被用来描述佛波醇的作用 酯类和炎症介质（例如缓激肽，P物质， 前列腺素E2）对β-AR-偶联腺苷酸环化酶系统的作用 分离的上皮细胞。最后，雾化过敏原对 该系统将在豚草致敏的兔和稳定的 人类哮喘患者。这些研究应该有助于阐明 调节正常上皮细胞中的β-AR偶联腺苷酸环化酶系统 细胞和从发炎的气道分离的细胞中。