Mechanisms of Anesthetic Effects on Tachykinin Induced Airway Tone

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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.