Nguyen Long P, Omoluabi Ozozoma, Parra Sergio, Frieske Joanna M, Clement Cecilia, Ammar-Aouchiche Zoulikha, Ho Samuel B, Ehre Camille, Kesimer Mehmet, Knoll Brian J, Tuvim Michael J, Dickey Burton F, Bond Richard A
Department of Pharmacological and Pharmaceutical Sciences, University of Houston, College of Pharmacy, 4800 Calhoun, Houston, TX 77204-5037, USA.
Am J Respir Cell Mol Biol. 2008 Mar;38(3):256-62. doi: 10.1165/rcmb.2007-0279RC. Epub 2007 Dec 20.
Single-dose administration of beta-adrenoceptor agonists produces bronchodilation and inhibits airway hyperresponsiveness (AHR), and is the standard treatment for the acute relief of asthma. However, chronic repetitive administration of beta-adrenoceptor agonists may increase AHR, airway inflammation, and risk of death. Based upon the paradigm shift that occurred with the use of beta-blockers in congestive heart failure, we previously determined that chronic administration of beta-blockers decreased AHR in a murine model of asthma. To elucidate the mechanisms for the beneficial effects of beta-blockers, we examined the effects of chronic administration of several beta-adrenoceptor ligands in a murine model of allergic asthma. Administration of beta-blockers resulted in a reduction in total cell counts, eosinophils, and the cytokines IL-13, IL-10, IL-5, and TGF-beta1 in bronchoalveolar lavage, and attenuated epithelial mucin content and morphologic changes. The differences in mucin content also occurred if the beta-blockers were administered only during the ovalbumin challenge phase, but administration of beta-blockers for 7 days was not as effective as administration for 28 days. These results indicate that in a murine model of asthma, chronic administration of beta-blockers reduces inflammation and mucous metaplasia, cardinal features of asthma that may contribute to airflow obstruction and AHR. Similar to heart failure, our results provide a second disease model in which beta-blockers producing an acutely detrimental effect may provide a therapeutically beneficial effect with chronic administration.
单剂量给予β-肾上腺素能受体激动剂可产生支气管扩张作用并抑制气道高反应性（AHR），是哮喘急性缓解期的标准治疗方法。然而，长期重复给予β-肾上腺素能受体激动剂可能会增加气道高反应性、气道炎症和死亡风险。基于在充血性心力衰竭中使用β受体阻滞剂所发生的模式转变，我们之前确定在哮喘小鼠模型中慢性给予β受体阻滞剂可降低气道高反应性。为了阐明β受体阻滞剂有益作用的机制，我们在过敏性哮喘小鼠模型中研究了几种β-肾上腺素能受体配体慢性给药的效果。给予β受体阻滞剂导致支气管肺泡灌洗中的总细胞计数、嗜酸性粒细胞以及细胞因子IL-13、IL-10、IL-5和TGF-β1减少，并减轻了上皮粘蛋白含量和形态学变化。如果仅在卵清蛋白激发阶段给予β受体阻滞剂，粘蛋白含量也会出现差异，但给予β受体阻滞剂7天的效果不如给予28天。这些结果表明，在哮喘小鼠模型中，慢性给予β受体阻滞剂可减轻炎症和粘液化生，这是哮喘的主要特征，可能导致气流阻塞和气道高反应性。与心力衰竭相似，我们的结果提供了第二个疾病模型，其中产生急性有害作用的β受体阻滞剂在慢性给药时可能具有治疗有益效果。
