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.
Chronic regular use of 2-adrenoceptor (2-AR) agonists in asthma is associated with a loss of disease control and increased risk of death. Conversely, we have found that administration of 2-AR inverse agonists results in attenuation of the asthma phenotype in an allergen-driven murine model. Besides antagonizing agonistinduced signaling and reducing signaling by empty receptors, -AR inverse agonists can also activate signaling by novel pathways. To determine the mechanism of the -AR inverse agonists, we compared the asthma phenotype in 2-AR-null and wild-type mice. Antigen challenge of 2-AR-null mice produced results similar to what was observed with chronic 2-AR inverse agonist treatment, namely, reductions in mucous metaplasia, airway hyperresponsiveness (AHR), and inflammatory cells in the lungs. These results indicate that the effects of 2-AR inverse agonists are caused by inhibition of 2-AR signaling rather than by the induction of novel signaling pathways. Chronic administration of alprenolol, a -blocker without inverse agonist properties, did not attenuate the asthma phenotype, suggesting that it is signaling by empty receptors, rather than agonist-induced 2-AR signaling, that supports the asthma phenotype. In conclusion, our results demonstrate that, in a murine model of asthma, 2-AR signaling is required for the full development of three cardinal features of asthma: mucous metaplasia, AHR, and the presence of inflammatory cells in the lungs.airway hyperresponsiveness ͉ -blocker ͉ inverse agonist ͉ mucous metaplasia ͉ inflammation
β(2)-Adrenoceptor (β2AR) agonists are the most effective class of bronchodilators and a mainstay of asthma management. The first potent β2AR agonist discovered and widely used in reversing the airway constriction associated with asthma exacerbation was the endogenous activator of the β2AR, epinephrine. In this study, we demonstrate that activation of the β2AR by epinephrine is paradoxically required for development of the asthma phenotype. In an antigen-driven model, mice sensitized and challenged with ovalbumin showed marked elevations in three cardinal features of the asthma phenotype: inflammatory cells in their bronchoalveolar lavage fluid, mucin over production, and airway hyperresponsiveness. However, genetic depletion of epinephrine using mice lacking the enzyme to synthesize epinephrine, phenylethanolamine N-methyltransferase, or mice that had undergone pharmacological sympathectomy with reserpine to deplete epinephrine, had complete attenuation of these three cardinal features of the asthma phenotype. Furthermore, administration of the long-acting β2AR agonist, formoterol, a drug currently used in asthma treatment, to phenylethanolamine N-methyltransferase-null mice restored the asthma phenotype. We conclude that β2AR agonist-induced activation is needed for pathogenesis of the asthma phenotype. These findings also rule out constitutive signaling by the β2AR as sufficient to drive the asthma phenotype, and may help explain why chronic administration of β2AR agonists, such as formoterol, have been associated with adverse outcomes in asthma. These data further support the hypothesis that chronic asthma management may be better served by treatment with certain "β-blockers."
These data suggest that in the murine model of asthma, several compensatory changes associated with either increased bronchodilator signaling or decreased bronchoconstrictive signaling, result from the chronic administration of certain 'beta-blockers'.
The mostly widely used bronchodilators in asthma therapy are β-adrenoreceptor (βAR) agonists, but their chronic use causes paradoxical adverse effects. We have previously determined that βAR activation is required for expression of the asthma phenotype in mice, but the cell types involved are unknown. We now demonstrate that βAR signaling in the airway epithelium is sufficient to mediate key features of the asthmatic responses to IL-13 in murine models. Our data show that inhibition of βAR signaling with an aerosolized antagonist attenuates airway hyperresponsiveness (AHR), eosinophilic inflammation, and mucus-production responses to IL-13, whereas treatment with an aerosolized agonist worsens these phenotypes, suggesting that βAR signaling on resident lung cells modulates the asthma phenotype. Labeling with a fluorescent βAR ligand shows the receptors are highly expressed in airway epithelium. In βAR mice, transgenic expression of βARs only in airway epithelium is sufficient to rescue IL-13-induced AHR, inflammation, and mucus production, and transgenic overexpression in WT mice exacerbates these phenotypes. Knockout of β-arrestin-2 (βarr-2) attenuates the asthma phenotype as in βAR mice. In contrast to eosinophilic inflammation, neutrophilic inflammation was not promoted by βAR signaling. Together, these results suggest βARs on airway epithelial cells promote the asthma phenotype and that the proinflammatory pathway downstream of the βAR involves βarr-2. These results identify βAR signaling in the airway epithelium as capable of controlling integrated responses to IL-13 and affecting the function of other cell types such as airway smooth muscle cells.
Glucocorticosteroids are the mainstay treatment for chronic asthma; however, adverse effects can limit their usefulness. We previously determined in experimental asthma that chronic administration of β₂-adrenoceptor inverse agonists reduced airway hyperresponsiveness and indexes of inflammation. However, the effect of co-administration of glucocorticosteroids with β₂-adrenoceptor inverse agonists is unknown. Therefore, we evaluated the anti-inflammatory effect of co-administration of dexamethasone, a glucocorticosteroid, and nadolol, a β₂-inverse agonist, in a murine asthma model. We measured eosinophils and cytokines in bronchoalveolar lavage fluid and mucin content in epithelial cells after exposure to different concentrations of dexamethasone and nadolol. Dexamethasone was administered for 3 days and nadolol for 24 days prior to ovalbumin challenge. Both drugs were continued during five daily intranasal challenges with ovalbumin. Independent administration of dexamethasone (0.4 mg/kg/day) or nadolol (25 ppm) reduced bronchoalveolar lavage eosinophils by 58% and 36%, respectively (P < 0.05). Co-administration of both drugs yielded an additive reduction in eosinophils (81%, P < 0.05). Co-administration of both drugs (dexamethasone 0.4 mg/kg/day and nadolol 25 ppm) also yielded a greater reduction in mucin volume density (83%) than either drug alone (18% for dexamethasone and 62% for nadolol) and greater than high-dose dexamethasone (71%) alone (P < 0.05). Similarly, co-administration of both drugs (dexamethasone 0.4 mg/kg/day and nadolol 25 ppm) yielded an additive effect on the reduction of type 2 cytokines in bronchoalveolar lavage fluid equivalent to the administration of a 10-fold higher dose of dexamethasone. In Summary, the simultaneous administration of a glucocorticosteroid and a β₂-adrenoceptor inverse agonist was more effective at reducing indexes of airway inflammation than either drug given alone; suggesting nadolol may possess "glucocorticoid-sparing" properties.
Based upon analogies to recent changes in the treatment of heart failure, we previously showed that chronic administration of certain ‘beta‐blockers’ decreased airway hyperresponsiveness (AHR) in a murine model of allergic asthma. To elucidate the mechanism for the beneficial effects, we used the same murine model to examine the effects of chronic administration of beta‐blockers on inflammation and mucous metaplasia, cardinal features of asthma that may contribute to AHR. Chronic administration of beta‐blockers reduced the total cell counts and eosinophils in bronchoalveolar lavage (BAL) of antigen‐challenged and sensitized mice. There was also reduced mucin production and goblet cell formation (mucous metaplasia) as determined by periodic acid Schiff's staining. A similar effect was observed by a second laboratory using a different strain of mice (C57BL/6J instead of BALB/cJ), with ~ 90% reduction in eosinophils and mucous metaplasia. These results were confirmed by a decrease in Muc5AC staining of airway epithelium using immunohistochemistry and Muc5AC transcript levels. BAL cytokine levels of IL‐13, IL‐10, IL‐5, and TGF‐â1 were also decreased. These observations suggest that asthmatics may benefit from treatment with beta‐blockers given their ability to reduce various indices of airway inflammation including mucous metaplasia, and inflammatory cells and cytokines in BAL.
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