Mechanisms of beta-blocker induced improvements in asthma

哮喘以气道阻塞、气道高反应性（AHR）和气道炎症为特征。用于控制和急性缓解哮喘的药物可能在有效性上有所不同，并产生严重的副作用。此外，约30%的哮喘患者没有达到任何治疗的最佳控制。 （SS） (/) 现状 <0 在哮喘模型中，我们已经表明13-受体阻滞剂的长期（28天）给药降低了AHR并产生了广泛的抗炎作用，包括气道上皮的显著变化：粘液产生减少，形态改善和I32AR产生增加。这些数据表明，气道上皮细胞可能是受慢性13受体阻滞剂治疗影响的关键靶点。此外，在一项用非选择性13-受体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，P020乙酰甲胆碱呈剂量依赖性增加，导致用40 mg纳多洛尔治疗的患者剂量增加> 2倍。我们的长期目标是开发13受体阻滞剂作为哮喘的替代疗法。为了在这方面取得进展，我们需要了解它们的作用机制。在这个项目中，我们将测试 "-w '<v 七世 0.-. v？， VII 假设13-阻断剂通过132AR影响气道上皮发挥其治疗作用。原提案的范围缩小了，将只包括我们已经取得进展的目标，并将最好地支持提交续期申请：具体而言，我们将：（1）。使用基因改变的小鼠来确定过敏性哮喘小鼠模型中受13-受体阻滞剂影响的关键细胞类型，和（2）。使用多种遗传学和生物化学方法，确定慢性13-受体阻滞剂对体外生长的气道上皮细胞中特定炎症信号转导通路的影响。 3-0 CD- c）" M = 3 （c）） PHS 398/2590（Rev.11/07） 第3页 m 续页格式 o.. 32¿ 目前使用的药物。因此，需要开发新的和更好的哮喘药物。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β受体阻滞剂是否对哮喘有益。使用鼠抗原驱动的 3 =（n " 0 Moo + L ' 0p.，>_E off ' :.（n个 ECM （二） :.. O-0 - - （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-: