Role of airway epithelial Beta2-adrenergic receptors

描述（由申请人提供）：已经证实，在气道平滑肌（ASM）细胞上激活β 2-肾上腺素能受体（(β 2ar)）可降低支气管运动性张力。鲜为人知的是，支气管上皮细胞比ASM具有更高的（beta2ar）密度，并且对原代和永生化气道上皮细胞的体外研究已经确定了能够引起ASM松弛的cAMP敏感机制。相反，使用完整上皮和脱落气管管的离体研究表明，上皮通过作为扩散屏障阻碍β -激动剂介导的ASM松弛，限制β -激动剂进入ASM （2ARs）。因此，基于细胞的关于上皮β 2ARs的体外实验结果尚未转化为动物模型的生理相关机制，也没有数据表明上皮β 2ARs参与哮喘患者支气管运动性张力的调节。由于对上皮β 2ars缺乏共识，导致哮喘的一种范式假设，默认情况下，β激动剂仅通过激活ASM上的β 2ars来影响支气管扩张。我们发现它惊人的位置和作用机制的关键治疗方式哮喘，吸入β激动剂，是不确定的。

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.