Mechanisms of beta-blocker induced improvements in asthma

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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-: