Role of airway epithelial Beta2-adrenergic receptors

气道上皮β2-肾上腺素能受体的作用

• 批准号: 6941678
• 负责人: Phillip H Factor
• 金额: $ 36.79万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-18 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6941678
• 关键词: allergens; beta adrenergic receptor; biological models; bronchus; catecholamines; cell membrane; chemosensitizing agent; gene deletion mutation; immunocytochemistry; inflammation; laboratory mouse; lung disorder; model design /development; nitric oxide; phosphorylation; polymerase chain reaction; prostaglandin E; protein structure function; receptor expression; respiratory airway pressure; respiratory epithelium; respiratory function; transfection

DESCRIPTION (provided by applicant): It is well established that activation of beta2-adrenergic receptors ((beta2AR) on airway smooth muscle (ASM) cells decreases bronchomotor tone. Less well appreciated is that bronchial epithelial cells have a higher density of (beta2ARs than do ASM and that in vitro studies of primary and immortalized airway epithelial cells have identified cAMP sensitive mechanisms capable of causing ASM relaxation. Conversely, ex vivo studies using epithelium intact and denuded tracheal tubes suggest that the epithelium impedes beta-agonist mediated ASM relaxation by serving as diffusion barrier that limits access of beta-agonists to ASM (2ARs. Thus, the results of cell-based in vitro experiments regarding epithelial (2ARs have not translated into physiologically relevant mechanisms in animal models nor are there data to suggest that epithelial beta2ARs participate in the regulation of bronchomotor tone in humans with asthma. This lack of consensus about epithelial beta2ARs has resulted in a paradigm of asthma that assumes, by default, that beta-agonists affect bronchodilation solely via activation of beta2ARs on ASM. We find it striking that the location and mechanism of action of a key therapeutic modality for asthma, inhaled beta-agonists, are uncertain. The absence of a defined role for epithelial beta2ARs, stems from the inability of prior in vivo studies to separate the physiologic effects of epithelial (beta2ARs from the direct bronchodilating effects of ASM beta2ARs. We believe that resolution of the role of epithelial beta2ARs could improve our understanding of reactive airway disease and better define how beta-agonists interacts with the airway to reduce airway reactivity. We have conducted preliminary experiments in which we observed that overexpression of a human beta2ARs cDNA in the airway epithelium of normal mice confers substantial protection from methacholine-induced bronchospasm. We also noted that the absence or inhibition of epithelial beta2ARs significantly increases airway reactivity in mice. These observations have caused us to hypothesize that: Bronchial epithelial beta2ARs participate in the regulation of airway reactivity. The lack of consensus regarding bronchial epithelial (2ARs and our ongoing studies of alveolar beta2ARs have led us to several questions regarding airway epithelial beta2ARs: 1) Do airway epithelial (2ARs regulate airway reactivity in normal mice? 2) Does agonist-induced receptor desensitization of epithelial beta2ARs affect airway reactivity? and 3) Does bronchopulmonary inflammation affect epithelial beta2ARs function? To address our hypothesis and questions we have structured 3 inter-related scientific aims that merge molecular tools with in vivo models to help repair the long-standing gap in knowledge regarding the role of epithelial beta2ARs. These studies will tell us how beta2ARs interact with catecholamines, if they affect airway reactivity, and whether they are affected by bronchopulmonary inflammation. We believe that confirmation of an important role for epithelial beta2ARs could justify the development of epithelial cell specific, gene-based, therapies that positively modulate epithelial beta-receptor function to produce sustained protection from bronchospastic challenges. Such therapies could significantly improve the health of patients with asthma.

DESCRIPTION (provided by applicant): It is well established that activation of beta2-adrenergic receptors ((beta2AR) on airway smooth muscle (ASM) cells decreases bronchomotor tone. Less well appreciated is that bronchial epithelial cells have a higher density of (beta2ARs than do ASM and that in vitro studies of primary and immortalized airway epithelial cells have identified cAMP sensitive mechanisms capable of相反，引起ASM放松。使用上皮完整的研究和裸露的气管导管表明，上皮会阻碍β激动剂通过作为扩散屏障的β-激动剂，以限制beta激动剂的访问权限，从而限制了β-激动剂对ASM的访问（2ARS）。是否有数据表明，上皮beta2ar参与了哮喘的人体支气管张力的调节。哮喘，吸入β-激动剂的治疗方式不确定。 上皮β2AR缺乏明确的作用，这是由于先前的体内研究无法分离上皮的生理效应（来自ASM Beta2ar的直接支气管调节作用的beta2ars的生理效应。我们相信，我们相信上皮beta2ar的作用的分解可以改善对反应性疾病的反应性疾病的理解，以使beta的相互作用与beta的相互作用相互作用。我们进行了初步实验，我们观察到正常小鼠的气道上皮的过表达，可以使甲基酚诱导的支气管痉挛的大量保护，我们还注意到缺乏或抑制了这些植物的反应。参与气道反应性的调节。 缺乏关于支气管上皮的共识（2ARS和我们正在进行的对肺泡β2AR的研究导致我们提出了有关气道上皮beta2ar的几个问题：1）气道上皮（2ARS调节正常鼠标中的气道反应性？ 3）支气管肺炎症会影响上皮β2AR的功能吗？ 为了解决我们的假设和问题，我们结构了3种相互关联的科学目的，将分子工具与体内模型合并，以帮助修复有关上皮beta2ars的作用的长期差距。 这些研究将告诉我们Beta2ARS如何与儿茶酚胺相互作用，是否影响气道反应性，以及它们是否受到支气管肺炎的影响。 我们认为，确认上皮beta2ar的重要作用可以证明上皮细胞特异性，基于基因的，基于基因的疗法的发展，这些疗法正阳性地调节上皮β受体功能，从而持续保护免受支气管疗法挑战的保护。 这种疗法可以显着改善哮喘患者的健康状况。