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

Abstract

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 betablockers 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-b1 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.

β 2 -Adrenoceptor signaling is required for the development of an asthma phenotype in a murine model

“…1 A). These results are similar to what we observed with the BALB/c and C57B/6J mice (14). In the FVB/N ␤ 2 -AR Ϫ/Ϫ mice group, antigen challenge produced significantly lower mucin volume density (P Ͻ 0.05) compared with antigen-challenged FVB/N mice and lower than in FVB/N mice treated with nadolol (P Ͻ 0.05) (Fig.…”

“…We have reported that chronic treatment with ␤ 2 -AR inverse agonists results in reductions of AHR, mucous metaplasia, and inflammatory cells in BALF (14,15). Here, we report that targeted disruption of the ␤ 2 -AR gene or chronic treatment with a ␤-blocker with inverse agonist properties at the ␤ 2 -AR both produce comparable attenuation of the asthma-like phenotype in a murine antigen-driven model of asthma.…”

“…Our previous studies were performed by using BALB/c and C57BL/6J mice (14), whereas the ␤ 2 -AR Ϫ/Ϫ mouse was constructed in the wild-type FVB/N background (21). Minimal intracellular mucin was observed in saline-challenged FVB/N mice assessed by using periodic acid f luorescent Schiff (PAFS) staining, whereas in antigenchallenged FVB/N mice there was abundant intracellular mucin (Fig.…”

“…Based on the paradigm shift that occurred in chronic CHF therapy, we investigated whether chronic treatment with ␤ 2 -AR inverse agonists, a class of drugs currently contraindicated in asthma because of their potential to produce acute bronchoconstriction, may be beneficial with long-term administration (14,15,25,26). Indeed, we found that chronic treatment with ␤ 2 -AR inverse agonists produced a time-dependent decrease in AHR and mucous metaplasia in a murine model of asthma (14,15), whereas treatment with alprenolol, a ␤-blocker without inverse agonist properties, did not decrease AHR (15).…”

“…Based on the clinical effects of ␤-blockers in CHF, we hypothesized that the chronic effects of ␤-blockers in asthma may be different from those observed during their acute administration (13). In previous studies, we chronically administered ␤-blockers with inverse agonist properties in a wellestablished antigen-driven murine asthma model and observed a significant decrease in epithelial cell mucous metaplasia, AHR, and airway inflammation (14,15). ␤-AR inverse agonists are a subset of ␤-blockers that in addition to inhibiting ␤-AR agonistinduced signaling also inhibit signaling produced by spontaneously or constitutively active receptors (16).…”