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Chronic Exposure to Beta-Blockers Attenuates Inflammation and Mucin Content in a Murine Asthma Model

¹ Department of Pharmacological and Pharmaceutical Sciences, and ² Department of Biology and Biochemistry, University of Houston, Houston, Texas; ³ Department of Pulmonary Medicine, M.D. Anderson Cancer Center, Houston, Texas; ⁴ Institute of Biosciences and Technology, Texas A&M University System Houston Health Science Center, Houston, Texas; ⁵ Department of Medicine, Veterans Affairs San Diego Healthcare System and University of California, San Diego, California; and ⁶ Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina, Chapel Hill, North Carolina

Correspondence and requests for reprints should be addressed to Richard A. Bond, Ph.D, Department of Pharmacological and Pharmaceutical Sciences, University of Houston, College of Pharmacy, 4800 Calhoun, Houston, TX 77204-5037. E-mail: RABond{at}uh.edu

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-β1 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.

Key Words: beta-blockers • beta-adrenoceptor • asthma • mucin • airway inflammation

CLINICAL RELEVANCE This research may result in a paradigm shift in the treatment of asthma. This research demonstrates the importance that duration of beta-blocker therapy has on clinical and physiologic responses.