Mechanisms of Anesthetic Effects on Tachykinin Induced Airway Tone

描述（由申请人提供）：哮喘是一种气道慢性炎症性疾病，其全球流行率已达到大流行的比例。虽然研究在阐明哮喘的潜在机制方面取得了很大进展，但近几十年来，对这种疾病的药理学治疗方法的新增加相对较少。我们的实验室有了几个新的发现：（1）3-氨基丁酸亚型A（GABAA）GABAA受体在气道平滑肌细胞上表达，（2）气道中存在内源性GABA能配体-受体系统，（3）内源性气道平滑肌GABAA受体的激活增强舒张，（4）GABA（内源性存在于气道中）起调节气道平滑肌张力的作用，（5）全身施用体内施用的GABAa受体激动剂减弱激动剂诱导的气道收缩，以及（6）异丙酚的支气管舒张作用的一部分是由气道平滑肌上的GABAA受体介导的。由于针对GABAa受体的配体/激动剂的药理学特异性由GABAa亚基组成决定，因此限制于给定组织的某些亚基的选择性靶向有望改善治疗。因此，我们的目标是阐明气道平滑肌GABAA受体亚单位组成对气道平滑肌张力调节的重要性。我们以前证明，人气道平滑肌表达有限的，但高度保守的GABAA受体亚基（包括14，15，23，32和42。这种有限的亚基库是有利的，因为它可以允许高度选择性靶向在气道平滑肌上表达的GABAA）受体。 令人兴奋的初步数据产生的这一建议支持的中心假设，气道上皮细胞是一个重要的细胞来源的气道GABA。它通过激酶调节的GABA转运蛋白（GAT 2和GAT 4/BGT-1）从上皮细胞释放，作用于气道平滑肌细胞上含有14和/或15的GABAA受体，以促进松弛。这些发现提供了一个激进的新疗法，一个翻译的治疗方法和一个新的范例，气道上皮细胞和平滑肌之间的旁分泌相互作用，以放松气道收缩。 公共卫生相关性：这些研究要解决的中心假设是气道上皮是气道GABA的细胞来源，气道GABA通过激酶调节的GABA转运蛋白（GAT 2和GAT 4/BGT-1）从上皮细胞释放。这种释放的GABA然后可以作用于气道平滑肌细胞上含有14和/或15的GABAA受体以促进松弛。我们计划确定新的14或15个亚基选择性激动剂，可以通过气雾剂输送到气道，以促进气道舒张。这些发现提供了一个激进的新疗法，一个翻译的治疗方法和一个新的范例，气道上皮细胞和平滑肌之间的旁分泌相互作用，以放松气道收缩。

DESCRIPTION (provided by applicant): Asthma is a chronic inflammatory disease of the airways whose global prevalence has taken on pandemic proportions. Although research has made great strides in elucidating the underlying mechanisms involved in asthma, in recent decades relatively few new additions have been made to the pharmacological armamentarium for this disease. Our laboratory has made several novel discoveries: (1) that 3-aminobutyric acid subtype A (GABAA) GABAA receptors are expressed on airway smooth muscle cells, (2) that an endogenous GABAergic ligand-receptor system exists in the airway, (3) that activation of endogenous airway smooth muscle GABAA receptors potentiates relaxation, (4) that GABA (endogenously present in the airway) functions to modulate airway smooth muscle tone, (5) that systemic administration of a GABAA receptor agonist administered in vivo attenuates agonist-induced airway constriction and that (6) part of propofol's broncho-relaxant effect is mediated by GABAA receptors on airway smooth muscle. Since pharmacologic specificity of ligands/agonists directed at the GABAA receptor is dictated by GABAA subunit composition, selective targeting of certain subunits restricted to a given tissue hold promise for improved therapy. Therefore, our goal is to elucidate the importance of airway smooth muscle GABAA receptor subunit composition on the modulation of airway smooth muscle tone. We previously demonstrated that human airway smooth muscle expresses a limited, yet highly conserved repertoire of GABAA receptor subunits (including 14, 15, 23, 32 and 42. This limited repertoire of subunits is advantageous, as it may allow for highly selective targeting of GABAA ) receptors expressed on airway smooth muscle. Exciting preliminary data generated for this proposal support the central hypothesis that airway epithelium is an important cellular source for airway GABA. It is released from epithelial cells via kinase- regulated GABA transporters (GAT2 and GAT4/BGT-1) to act upon 14- and/or 15 containing GABAA receptors on airway smooth muscle cells to facilitate relaxation. These findings offer a radical new therapy, a translational therapeutic approach and a novel paradigm for paracrine interactions between airway epithelium and smooth muscle for relaxing airway constriction. PUBLIC HEALTH RELEVANCE: The central hypotheses to be addressed by the studies are that airway epithelium is a cellular source for airway GABA that is released from epithelial cells via kinase-regulated GABA transporters (GAT2 and GAT4/BGT-1). This released GABA can then act upon 14- and/or 15 containing GABAA receptors on airway smooth muscle cells to facilitate relaxation. We plan to identify novel 14 or 15 subunit-selective agonists that can be delivered to airways by aerosol to facilitate airway relaxation. These findings offer a radical new therapy, a translational therapeutic approach and a novel paradigm for paracrine interactions between airway epithelium and smooth muscle for relaxing airway constriction.