CORTICOSTEROID EFFECT ON AIRWAY BETA-ADRENERGIC FUNCTION

皮质类固醇是有效的抗炎药，但特异性 其治疗作用的分子机制研究进展 哮喘的治疗方法仍有待确定。历史悠久的临床 观察表明，糖皮质激素可能协同作用于 增强对β-肾上腺素能I激动剂的呼吸道松弛反应，以及 新的证据表明，皮质类固醇可以调节多种 决定呼吸道平滑肌程度的细胞蛋白 放松一下。这些信息，结合独立的观察结果， 呼吸道对松弛的β-肾上腺素能药物的反应在 出生后发展，提出了两个相互关联的假说： 皮质类固醇调节特定的β-肾上腺素能受体偶联和 受体后转导机制对气道平滑肌的调节作用 松弛；以及ii.糖皮质激素对这些的影响 机制随年龄的变化而变化。在解决这些问题时 假设，皮质类固醇对呼吸道β-肾上腺素能的影响 功能将在从新生儿和成人分离的组织中进行评估 兔子。确定皮质类固醇是否调节呼吸道 β-肾上腺素能反应性，类固醇效应将通过 关于调节：1)对β-肾上腺素受体的反应性 急性(即1-6小时)或慢性治疗的组织中的刺激 (例如，24-48小时)；2)代谢途径 β-肾上腺素能激动剂；3)β-肾上腺素受体放射配基结合 密度与药理受体储备；4)β-肾上腺素能亲和力 受体激动剂；5)受体后介导的腺苷激活 6)抑制性(G1)和刺激性(G)鸟嘌呤的影响 调节蛋白，通过功能和特定标记进行分析 7)生电Na(+)-K(-)-的相对贡献 泵连接到β-肾上腺素受体刺激；以及8)合成 β肾上腺素受体和Na(+)-K(-)泵蛋白的变化 Northern印迹分析检测到特定的mRNA水平。在单独的 研究，出生后成熟对皮质激素诱导的影响 对气道平滑肌松弛的调节将进一步用 关于上述机制中与年龄有关的变化。总体而言， 拟议的研究将对这一机制产生重要的新见解 皮质类固醇对呼吸道β-肾上腺素能的调节作用 响应性，从而最终为 更直接的方法治疗哮喘的支气管痉挛。

Corticosteroids are potent anti-inflammatory agents, but the specific molecular 1 mechanisms accounting for their therapeutic efficacy in the treatment of asthma remain to be identified. Long-standing clinical observation suggests that glucocorticoids may@, act synergistically to potentiate the airway relaxant response to beta-adrenergic I agonists, and emerging evidence indicates that corticosteroids can regulate various cellular proteins that determine the degree of airway smooth muscle relaxation. This information, combined with independent observations that the airway's response to relaxant beta-adrenergic agents varies during post-natal development, raises two interrelates hypotheses: I. That corticosteroids modulate specific beta-adrenergic receptor-coupled and post-receptor transduction mechanisms regulating airway smooth muscle relaxation; and II. That the influence of glucocorticoids on these mechanisms varies in an age-dependent manner. In addressing these hypotheses, the influence of corticosteroids on airway beta-adrenergic function will be assessed in tissues isolated from newborn and adult rabbits. To determine whether corticosteroids modulate airway beta-adrenergic responsiveness, steroid effects will be examined with respect to modulation of: 1) responsiveness to beta-adrenoreceptor stimulation in tissues treated acutely (i.e., 1-6 hrs) or chronically (i.e., 24-48 hrs) with corticosteroids; 2) degradation pathways of beta-adrenergic agonists; 3) beta-adrenoreceptor radioligand-binding density and pharmacologic receptor reserve; 4) affinity of beta-adrenergic agonists to the receptor; 5) post-receptor mediated activation of adenylate cyclase; 6) the influence of inhibitory (G1) and stimulatory (G) guanine regulatory proteins, assayed both functionally and by specific labelling techniques; 7) the relative contribution of the electrogenic Na(+)-K(-) - pump coupled to beta-adrenoreceptor stimulation; and 8) synthesis of beta-adrenoreceptor and Na(+)-K(-) pump proteins, as indicated by changes in specific MRNA levels measured by Northern blot analysis. In separate studies, the influence of post-natal maturation on corticosteroid-induced modulation of airway smooth muscle relaxation will be further examined with respect to age-related changes in the above mechanisms. Collectively, the proposed studies will yield significant new insights into the mechanisms underlying corticosteroid-induced modulation of airway beta-adrenergic responsiveness and, thereby, ultimately provide a scientific basis for a more directed approach to the treatment of the bronchospasm in asthma.