Mechanisms of Anesthetic Effects on Tachykinin Induced Airway Tone

描述(申请人提供)：哮喘是一种慢性呼吸道炎症性疾病，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，治疗这种疾病的药理工具相对较少。我们的实验室有一些新的发现：(1)3-氨基丁酸A亚型(GABAA)GABAA受体表达于气道平滑肌细胞上，(2)内源性GABAA能配体-受体系统存在于气道中，(3)激活内源性GABAA受体可增强松弛，(4)GABA(内源性存在于气道)具有调节气道平滑肌张力的功能，(5)全身应用GABAA受体激动剂可减轻激动剂诱导的气道收缩，(6)异丙酚的部分支气管松弛作用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，选择性靶向特定的亚基限制在给定的组织中有望改善治疗。因此，我们的目标是阐明气道平滑肌GABAA受体亚单位组成在调节气道平滑肌张力中的重要性。我们先前已经证明，人的呼吸道平滑肌表达有限但高度保守的GABAA受体亚基(包括14、15、23、32和42)。这种有限的亚基谱系是有利的，因为它可以高度选择性地靶向表达在呼吸道平滑肌上的GABAA)受体。为这一提议产生的令人兴奋的初步数据支持了这样的中心假设，即呼吸道上皮是呼吸道GABA的重要细胞来源。它通过激酶调节的GABA转运体(GAT2和GAT4/BGT-1)从上皮细胞释放出来，作用于呼吸道平滑肌细胞上含有14和/或15个GABAA受体的受体，以促进松弛。这些发现提供了一种根本性的新疗法、一种转化性治疗方法和一种新的范式，即通过呼吸道上皮和平滑肌之间的旁分泌相互作用来缓解气道收缩。

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.