CORTICOSTEROID EFFECT ON AIRWAY BETA-ADRENERGIC FUNCTION

皮质类固醇是有效的抗炎剂，但具体 分子1机制解释了它们在 哮喘的治疗仍有待确定。长期临床 观察表明，糖皮质激素可能协同作用， 增强对β-肾上腺素能I激动剂的气道舒张反应，和 新出现的证据表明，皮质类固醇可以调节各种 决定气道平滑肌 放松.这些信息，加上独立观察， 气道对松弛剂β-肾上腺素能药物的反应在 出生后发育，提出了两个相互关联的假说：I.的 皮质类固醇调节特异性β-肾上腺素能受体偶联， 调节气道平滑肌的受体后转导机制 放松;和II.糖皮质激素对这些细胞的影响 机制以年龄依赖的方式变化。在解决这些 假设，皮质类固醇对气道β-肾上腺素能 将在从新生儿和成人分离的组织中评估功能 家兔确定皮质类固醇是否调节气道 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 急性治疗的组织中的刺激（即，1-6小时）或长期 (i.e., 24-48小时）; 2） β-肾上腺素能激动剂; 3）β-肾上腺素受体放射性配体结合 密度和药理学受体储备; 4）β-肾上腺素能受体的亲和力 受体激动剂; 5）受体后介导的腺苷酸活化 环化酶; 6）抑制性（G1）和刺激性（G）鸟嘌呤的影响 调节蛋白，功能性和特异性标记测定 7）产电Na（+）-K（-）- 与β-肾上腺素受体刺激偶联的泵;和8）合成 β-肾上腺素受体和Na（+）-K（-）泵蛋白，如变化所示 通过北方印迹分析测量的特定mRNA水平。分开的 研究，出生后成熟对皮质类固醇诱导的 气道平滑肌松弛的调节将进一步用 上述机制中与年龄相关的变化。统称 拟议的研究将产生重要的新见解的机制， 皮质类固醇诱导的气道β-肾上腺素能调节 反应能力，从而最终为一个 更直接的方法来治疗支气管痉挛的哮喘。

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.