Mechanisms of beta-blocker induced improvements in asthma

哮喘的特征是呼吸道阻塞、气道高反应性(AHR)和呼吸道炎症。用于控制和急性缓解哮喘的药物可能效果不同，并产生严重的副作用。此外，-30%的哮喘患者在任何情况下都无法实现最佳控制 (SS) (/) 现状 *&lt；0 在哮喘模型上，我们发现长期(28天)应用13-受体阻滞剂可降低AHR并产生广泛的抗炎作用，包括呼吸道上皮细胞的显著变化：粘液生成减少，形态改善，I32ARs生成增加。这些数据表明，呼吸道上皮细胞可能是慢性13-受体阻滞剂治疗的关键靶点。此外，在用非选择性13-阻滞剂纳多洛尔治疗10名轻度哮喘患者的小型临床试验中，服用40毫克纳多洛尔的患者的P020乙酰甲胆碱水平呈剂量依赖性增加，导致&gt；剂量增加两倍。我们的长期目标是开发13种阻滞剂作为哮喘的替代疗法。为了在这一翻译方面取得进展，我们需要了解他们的行动机制。在这个项目中，我们将测试 “-w (&L；V) Vii‘ 0.-。 V？， 第七章 13-受体阻滞剂通过132ARs影响呼吸道上皮细胞发挥治疗作用的假说。原建议的范围有所缩小，将只包括我们已经取得进展并将最好地支持提交续期申请的目标：具体而言，我们将：(1)。使用基因改变的小鼠来确定13-阻滞剂在过敏性哮喘小鼠模型中影响的关键细胞类型，以及(2)。采用多种遗传学和生物化学方法，确定慢性13-受体阻滞剂对体外培养的呼吸道上皮细胞炎症信号转导通路的影响。 3-0 CD- C)‘ M=3 (C)) PHS 398/2590(11/07版) 第3页 ？-m 续订格式页面 不..？ 32？ 目前使用的药物。因此，有必要开发治疗哮喘的新的更好的药物。基于在心力衰竭中使用I3AR激动剂和拮抗剂所发生的范式转变，我们测试了长期给予3-受体阻滞剂是否对哮喘有益。使用由小鼠抗原驱动的 3=(n‘ 0 Moo +L OP.、&gt；_E 关‘ ：。(n ECM (Ii) ：. O-0 O-- (Q‘ 6C‘ 0-：

Asthma is characterized by airway obstruction, airway hyperresponsiveness (AHR) and airway inflammation. The medications used for control and acute relief of asthma may vary in effectiveness and produce serious side effects. Also, -30% of asthma patients do not achieve optimal control with any of the (SS (/) Quo ¿<0 model of asthma, we have shown that chronic (28 day) administration of 13-blockers decreased AHR and produced broad anti-inflammatory effects, including dramatic changes in airway epithelium: reduced mucous production, improved morphology and increased production of I32ARs. These data suggest that the airway epithelium may be a key target affected by chronic 13-blocker therapy. Also, in a small clinical trial treating 10 mild asthmatics with the non-selective 13-blocker, nadolol, there was a dose-dependent increase in the P020 methacholine that resulted in a change of> two doubling doses in patients treated with 40 mg of nadolol. Our long-range goal is to develop 13-blockers as an alternative therapy for asthma. To make progress towards this translation, we need to understand their mechanisms of action. In this project, we will test the "-w ¿'<v vii' 0.-. v¿, vii hypothesis that 13-blockers influence airway epithelium via 132ARs to exert their therapeutic effects. The scope of the original proposal is reduced and will comprise only those aims in which we have already made progress and will best support the submission of a renewal application: Specifically, we will: (1). Use genetically altered mice to determine the critical cell type affected by 13-blockers in the mouse model of allergic asthma, and (2). Determine the effect of chronic 13-blocker on specific inflammatory signal transduction pathways in airway epithelium grown in vitro, using a variety of genetic and biochemical methods. 3-0 CD- c)' m=3 C)) PHS 398/2590 (Rev. 11/07) Page 3 ¿-m Continuation Format Page o..¿ 32¿ currently used medications. Thus, there is a need to develop new and better medications for asthma. Based on the paradigm shift that occurred with the use of I3AR agonists and antagonists in heart failure, we tested whether chronic (3-blocker administration may be beneficial in asthma. Using a murine antigen driven 3=(n' 0 moo +L' 0p., >_E Off' :.(n ECM (II :.. O-0 o-- (Q' 6C' 0-: