Mechanisms of Anesthetic Effects on Tachykinin Induced Airway Tone

描述（由申请人提供）：哮喘是一种慢性气道炎症性疾病，其全球患病率已达到大流行的程度。尽管研究在阐明哮喘的潜在机制方面取得了很大的进展，但近几十年来，针对这种疾病的药理学研究相对较少。我们实验室有几项新发现：(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GABAA能配体受体系统，(3)内源性气道平滑肌GABAA受体的激活增强松弛，(4)GABA（内源性存在于气道中）调节气道平滑肌张力，(5)体内全身给药GABAA受体激动剂可减轻激动剂诱导的气道收缩；(6)部分异丙酚的支气管松弛作用是由GABAA受体对气道平滑肌的作用介导的。由于针对GABAA受体的配体/激动剂的药理学特异性是由GABAA亚基组成决定的，因此对特定组织的特定亚基的选择性靶向治疗有望改善治疗。因此，我们的目的是阐明气道平滑肌GABAA受体亚基组成在气道平滑肌张力调节中的重要性。我们之前证明，人类气道平滑肌表达GABAA受体亚基有限，但高度保守的库（包括14、15、23、32和42）。这种有限的亚基库是有利的，因为它可能允许高度选择性靶向气道平滑肌上表达的GABAA)受体。这一提议产生的令人兴奋的初步数据支持了气道上皮是气道GABA的重要细胞来源的中心假设。它通过激酶调节的GABA转运体（GAT2和GAT4/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，促进松弛。这些发现为缓解气道收缩的气道上皮和平滑肌之间的旁分泌相互作用提供了一种全新的治疗方法、转化治疗方法和新范式。

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.